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1

Ecological Structure Activity Relationships  

EPA Science Inventory

Ecological Structure Activity Relationships, v1.00a, February 2009 ECOSAR (Ecological Structure Activity Relationships) is a personal computer software program that is used to estimate the toxicity of chemicals used in industry and discharged into water. The program predicts...

2

Structure-activity relationships of estrogens.  

PubMed Central

The last 50 years has seen an exponential rise in the published reports about estrogen action. The model to describe the early events in the mechanism of action of estrogens via the estrogen receptor is updated in this paper to incorporate some of the recent data on the subcellular localization of the receptor. New evidence suggests that the receptor is a nuclear protein, so it appears that estrogens must first diffuse into the nuclear compartment to initiate estrogen action via the receptor complex. This review traces the development of potent estrogenic compounds by the study of their structure-activity relationships. Studies of structure-activity relationships in vivo using Allen Doisy or 3-day uterine weight tests can provide much valuable information, but the assays suffer from the complex problems of pharmacokinetics and metabolic transformation. Studies in vitro using primary cultures of rat pituitary or uterine cells to assay the ability of a compound to induce prolactin synthesis or progesterone receptor synthesis, respectively, can provide essential information about the structural requirements for a compound to produce estrogenic effects. Nevertheless, it should be pointed out that studies in vivo are required to determine whether a compound is metabolically activated to an estrogen. Estrogen receptor binding models are presented to describe the changes in a molecule that will predict high affinity for the ligand and agonist, partial agonist and antagonist properties of the ligand-receptor complex. Most estrogenic pesticides and phytoestrogens comform to the predictions of the estrogen receptor binding model.

Jordan, V C; Mittal, S; Gosden, B; Koch, R; Lieberman, M E

1985-01-01

3

Cationic phospholipids: structure?transfection activity relationships  

SciTech Connect

Synthetic cationic lipids are presently the most widely used non-viral gene carriers. Examined here is a particularly attractive cationic lipid class, triester phosphatidylcholines (PCs) exhibiting low toxicities and good transfection efficiency. Similarly to other cationic lipids, they form stable complexes (lipoplexes) with the polyanionic nucleic acids. A summary of studies on a set of {approx}30 cationic PCs reveals the existence of a strong, systematic dependence of their transfection efficiency on the lipid hydrocarbon chain structure: transfection activity increases with increase of chain unsaturation from 0 to 2 double bonds per lipid and decreases with increase of chain length in the range {approx}30-50 total number of chain carbon atoms. Maximum transfection was observed for ethyl phosphate PCs (EPCs) with monounsaturated 14:1 chains (total of 2 double bonds and 30 chain carbon atoms). Lipid phase behavior is known to depend strongly on the chain molecular structure and the above relationships thus substantiate a view that cationic PC phase propensities are an important determinant of their activity. Indeed, X-ray structural studies show that the rate of DNA release from lipoplexes as well as transfection activity well correlate with non-lamellar phase progressions observed in cationic PC mixtures with membrane lipids. These findings appear to be of considerable interest because, according to current views, key processes in lipid-mediated transfection such as lipoplex disassembly and DNA release within the cells are believed to take place upon cationic lipid mixing with cellular lipids.

Koynova, Rumiana; Tenchov, Boris; (NWU)

2010-01-18

4

Structure-activity relationships in aquatic toxicology.  

PubMed

Relationships among chemical structure, aquatic toxicity, and bioconcentration potential were examined for several classes of organic compounds. Structure-toxicity correlations were based largely on median lethal concentrations (LC50) and toxicant threshold concentrations (LC1) determined in mini-chronic tests with early life stages of fish and amphibians. Exposure was initiated at fertilization and maintained through 4 days posthatching. Bioconcentration potential was assessed using n-octanol/water partition coefficients (log P). In tests with polychlorinated biphenyls (PCB), acute and chronic toxicity generally increased with percent chlorination. In addition, toxicity of specific PCB's appeared to be affected by the ratio of less chlorinated to more highly chlorinated isomers. The toxicity of chlorinated methanes (i.e., methylene chloride, chloroform, carbon tetrachloride) also increased with chlorination. Concerning single ring aromatic compounds, pyridine was much less toxic than benzene and benzene was less toxic than its mono-substituted derivatives, including chlorobenzene, nitrobenzene, toluene, and phenol. However, no consistent order of toxicity was observed for the substituted compounds. Acute toxicity also increased with the number of aromatic rings in a series of nitrogen heterocyclic compounds, and the latter were less toxic than corresponding alicyclic compounds. Within most classes of compounds, a direct correlation was observed between acute toxicity and bioconcentration potential. As observed with PCB compounds, the mini-chronic test described in this study permitted evaluations of structure-activity relationships using both LC50 and LC1 values determined with early life stages. The LC1's compared well with results obtained in life-cycle studies, thus providing an economical and reliable means of estimating chronic values for reproductive impairment. PMID:6416914

Birge, W J; Cassidy, R A

5

Structure-Activity Relationships of the Cannabinoids.  

National Technical Information Service (NTIS)

Presents current research on ways in which changing the molecular structure of natural cannabinoids (the active constituents of marijuana) and their synthetic analogs alters their effects. Because cannabinoids may have clinical applications, a research go...

A. Makriyannis R. S. Rapaka

1987-01-01

6

Structure activity relationships of selected naphthalene derivatives  

SciTech Connect

Twenty-two derivatives of naphthalene were assayed under an acute static regime with biological activity being monitored as population growth of Tetrahymena pyriformis. Activity varied over one log unit. Substituent constant structure-activity analyses revealed the model, log BR = 0.282Ha + 0.352..pi.. + 0.692F + 0.334/sup 1/X/sub sub//sup v/ - 0.326R + 0.027, to be best and to account for 85% of the variation in log BR (BR, biological response; Ha, hydrogen acceptance; ..pi.., hydrophobic substituent constant; F, polar electronic substituent constant, /sup 1/X/sub sub//sup v/, substituent molar connectivity index; R, resonance electronic substituent constant). The Ha and ..pi.. parameters are the most important, accounting for 71% of the log BR variability. 21 references, 1 figure, 7 tables.

Schultz, T.W.; Dumont, J.N.; Sankey, F.D.; Schmoyer, R.L. Jr.

1983-01-01

7

Structure-Activity Relationships of Agents Modifying Cholinergic Transmission.  

National Technical Information Service (NTIS)

Structure activity relationship studies of hemicholinium (HC-3) analogs are directed toward better understanding both the spatial aspect of the receptor interatomic distances between the 2 cationic heads. Several series of compounds including 4,4' bipheny...

J. P. Long R. K. Bhatnagar J. G. Cannon

1990-01-01

8

DEVELOPMENT OF STRUCTURE ACTIVITY RELATIONSHIPS FOR ASSESSING ECOLOGICAL RISKS  

EPA Science Inventory

In the field of environmental toxicology, structure activity relationships (SARs) have developed as scientifically-credible tools for predicting the effects of chemicals when little or no empirical data are available....

9

Divergent structure-activity relationships of structurally similar acetylcholinesterase inhibitors.  

PubMed

The molecular interactions between the enzyme acetylcholinesterase (AChE) and two compound classes consisting of N-[2-(diethylamino)ethyl]benzenesulfonamides and N-[2-(diethylamino)ethyl]benzenemethanesulfonamides have been investigated using organic synthesis, enzymatic assays, X-ray crystallography, and thermodynamic profiling. The inhibitors' aromatic properties were varied to establish structure-activity relationships (SAR) between the inhibitors and the peripheral anionic site (PAS) of AChE. The two structurally similar compound classes proved to have distinctly divergent SARs in terms of their inhibition capacity of AChE. Eight X-ray structures revealed that the two sets have different conformations in PAS. Furthermore, thermodynamic profiles of the binding between compounds and AChE revealed class-dependent differences of the entropy/enthalpy contributions to the free energy of binding. Further development of the entropy-favored compound class resulted in the synthesis of the most potent inhibitor and an extension beyond the established SARs. The divergent SARs will be utilized to develop reversible inhibitors of AChE into reactivators of nerve agent-inhibited AChE. PMID:23984975

Andersson, C David; Forsgren, Nina; Akfur, Christine; Allgardsson, Anders; Berg, Lotta; Engdahl, Cecilia; Qian, Weixing; Ekström, Fredrik; Linusson, Anna

2013-09-19

10

Structure–activity relationship of antibacterial chalcones  

Microsoft Academic Search

The antibacterial activity of 31 chalcones was tested against bacterial strains, Bacillus cereus ATCC 11778, Escherichia coli ATCC 25922, Pseudomonas aeruginosa ATCC 27853, and Staphylococcus aureus ATCC 25923. Some of the tested chalcones showed fair to significant activity against Gram-positive bacteria. By comparison of the results obtained, the antibacterial activity can be related to features such as the presence of

Hugo Pereira Ávila; Elza de Fátima Albino Smânia; Franco Delle Monache; Artur Smânia

2008-01-01

11

Quantitative structure–activity relationship study of antitubercular fluoroquinolones  

Microsoft Academic Search

Quantitative structure–activity relationship study on three diverse sets of structurally similar fluoroquinolones was performed\\u000a using a comprehensive set of molecular descriptors. Multiple linear regression technique was applied as a preprocessing tool\\u000a to find the set of relevant descriptors (10) which are subsequently used in the artificial neural networks approach (non-linear\\u000a procedure). The biological activity in the series (minimal inhibitory concentration

Nikola Minovski; Marjan Vra?ko; Tom Šolmajer

2011-01-01

12

Partitioning and lipophilicity in quantitative structure-activity relationships.  

PubMed Central

The history of the relationship of biological activity to partition coefficient and related properties is briefly reviewed. The dominance of partition coefficient in quantitation of structure-activity relationships is emphasized, although the importance of other factors is also demonstrated. Various mathematical models of in vivo transport and binding are discussed; most of these involve partitioning as the primary mechanism of transport. The models describe observed quantitative structure-activity relationships (QSARs) well on the whole, confirming that partitioning is of key importance in in vivo behavior of a xenobiotic. The partition coefficient is shown to correlate with numerous other parameters representing bulk, such as molecular weight, volume and surface area, parachor and calculated indices such as molecular connectivity; this is especially so for apolar molecules, because for polar molecules lipophilicity factors into both bulk and polar or hydrogen bonding components. The relationship of partition coefficient to chromatographic parameters is discussed, and it is shown that such parameters, which are often readily obtainable experimentally, can successfully supplant partition coefficient in QSARs. The relationship of aqueous solubility with partition coefficient is examined in detail. Correlations are observed, even with solid compounds, and these can be used to predict solubility. The additive/constitutive nature of partition coefficient is discussed extensively, as are the available schemes for the calculation of partition coefficient. Finally the use of partition coefficient to provide structural information is considered. It is shown that partition coefficient can be a valuable structural tool, especially if the enthalpy and entropy of partitioning are available.

Dearden, J C

1985-01-01

13

Capturing structure-activity relationships from chemogenomic spaces.  

PubMed

Modeling off-target effects is one major goal of chemical biology, particularly in its applications to drug discovery. Here, we describe a new approach that allows the extraction of structure-activity relationships from large chemogenomic spaces starting from a single chemical structure. Several public source databases, offering a vast amount of data on structure and activity for a large number of different targets, have been investigated for their usefulness in automated structure-activity relationships (SAR) extraction. SAR tables were constructed by assembling similar structures around each query structure that have an activity record for a particular target. Quantitative series enrichment analysis (QSEA) was applied to these SAR tables to identify trends and to transform these trends into topomer CoMFA models. Overall more than 1700 SAR tables with topomer CoMFA models have been obtained from the ChEMBL, PubChem, and ChemBank databases. These models were able to highlight the structural trends associated with various off-target effects of marketed drugs, including cases where other structural similarity metrics would not have detected an off-target effect. These results indicate the usefulness of the QSEA approach, particularly whenever applicable with public databases, in providing a new means, beyond a simple similarity between ligand structures, to capture SAR trends and thereby contribute to success in drug discovery. PMID:21410249

Wendt, Bernd; Uhrig, Ulrike; Bös, Fabian

2011-03-16

14

Structure-Activity Relationships on Compounds Having Neuro-Muscular Activity.  

National Technical Information Service (NTIS)

The report deals with the biological activity of four different series of compounds which were developed to clarify the structure-activity relationships required for optimal biological activity. Three of the series were carbamates with potent antiesterase...

T. A. Loomis

1974-01-01

15

(Quantitative structure-activity relationships in environmental toxicology)  

SciTech Connect

The traveler attended the Fourth International Workshop on QSAR (Quantitative Structure-Activity Relationships) in Environmental Toxicology. He was an author or co-author on one platform and two poster presentations. The subject of the workshop offers a framework for analyzing and predicting the fate of chemical pollutants in organisms and the environment. QSAR is highly relevant to the ORNL program on the physicochemical characterization of chemical pollutants for health protection.

Turner, J.E.

1990-10-04

16

Structure activity relationship studies of tricyclic bispyran sulfone ?-secretase inhibitors.  

PubMed

An investigation is detailed of the structure activity relationships (SAR) of two sulfone side chains of compound (-)-1a (SCH 900229), a potent, PS1-selective ?-secretase inhibitor and clinical candidate for the treatment of Alzheimer's disease. Specifically, 4-CF(3) and 4-Br substituted arylsulfone analogs, (-)-1b and (-)-1c, are equipotent to compound (-)-1a. On the right hand side chain, linker size and terminal substituents of the pendant sulfone group are also investigated. PMID:23265892

Wu, Wen-Lian; Asberom, Theodros; Bara, Thomas; Bennett, Chad; Burnett, Duane A; Clader, John; Domalski, Martin; Greenlee, William J; Josien, Hubert; McBriar, Mark; Rajagopalan, Murali; Vicarel, Monica; Xu, Ruo; Hyde, Lynn A; Del Vecchio, Robert A; Cohen-Williams, Mary E; Song, Lixin; Lee, Julie; Terracina, Giuseppe; Zhang, Qi; Nomeir, Amin; Parker, Eric M; Zhang, Lili

2012-11-24

17

Relationship between antimold activity and molecular structure of cinnamaldehyde analogues.  

PubMed

A quantitative structure-activity relationship (QSAR) modeling of the antimold activity of cinnamaldehyde analogues against of Aspergillus niger and Paecilomyces variotii was presented. The molecular descriptors of cinnamaldehyde analogues were calculated by the CODESSA program, and these descriptors were selected by best multi-linear regression method (BMLR). Satisfactory multilinear regression models of Aspergillus niger and Paecilomyces variotii were obtained with R(2)=0.9099 and 0.9444, respectively. The models were also satisfactorily validated using internal validation and leave one out validation. The QSAR models provide the guidance for further synthetic work. PMID:23374870

Zhang, Yuanyuan; Li, Shujun; Kong, Xianchao

2013-01-12

18

Quantitative structure–activity relationship (QSAR) for insecticides: development of predictive in vivo insecticide activity models  

Microsoft Academic Search

Quantitative structure–activity relationship (QSAR) analyses were performed independently on data sets belonging to two groups of insecticides, namely the organophosphates and carbamates. Several types of descriptors including topological, spatial, thermodynamic, information content, lead likeness and E-state indices were used to derive quantitative relationships between insecticide activities and structural properties of chemicals. A systematic search approach based on missing value, zero

P. K. Naik; Sindhura; T. Singh; H. Singh

2009-01-01

19

STRUCTURE-ACTIVITY RELATIONSHIP STUIDES AND THEIR ROLE IN PREDICTING AND INVESTIGATING CHEMICAL TOXICITY  

EPA Science Inventory

Structure-Activity Relationship Studies and their Role in Predicting and Investigating Chemical Toxicity Structure-activity relationships (SAR) represent attempts to generalize chemical information relative to biological activity for the twin purposes of generating insigh...

20

CONSIDERATION OF REACTION INTERMEDIATES IN STRUCTURE-ACTIVITY RELATIONSHIPS: A KEY TO UNDERSTANDING AND PREDICTION  

EPA Science Inventory

Consideration of Reaction Intermediates in Structure- Activity Relationships: A Key to Understanding and Prediction A structure-activity relationship (SAR) represents an empirical means for generalizing chemical information relative to biological activity, and is frequent...

21

Structure-activity relationship of kahalalide F synthetic analogues.  

PubMed

Kahalalide F (KF) is a natural product currently under phase II clinical trials. Here, we report the solid phase synthesis of 132 novel analogues of kahalalide F and their in vitro activity on a panel of up to 14 cancer cell lines. The structure-activity relationship of these analogues revealed that KF is highly sensitive to backbone stereotopical modification but not to side chain size modification. These observations suggest that this compound has a defined conformational structure and also that it interacts with chiral compounds through its backbone and not through its side chains. The N-terminal aliphatic acid appears to be a hydrophobic buoy in a membrane-like environment. Moreover, significant improvement of the in vitro activity was achieved. PMID:18672864

Jiménez, José C; López-Macià, Angel; Gracia, Carol; Varón, Sonia; Carrascal, Marta; Caba, Josep M; Royo, Miriam; Francesch, Andrés M; Cuevas, Carmen; Giralt, Ernest; Albericio, Fernando

2008-08-01

22

Antioxidant and prooxidant behavior of flavonoids: structure-activity relationships.  

PubMed

The antioxidant and prooxidant behavior of flavonoids and the related activity-structure relationships were investigated in this study using the oxygen radical absorbance capacity assay. Three different reactive species were used in the assay: 2,2'-azobis(2-amidino-propane) dihydrochloride, a peroxyl radical generator; Cu(2+)-H2O2, mainly a hydroxyl radical generator; and Cu2+, a transition metal. Flavonoids including flavones, isoflavones, and flavanones acted as antioxidants against peroxyl and hydroxyl radicals and served as prooxidants in the presence of Cu2+. Both the antioxidant and the copper-initiated prooxidant activities of a flavonoid depend upon the number of hydroxyl substitutions in its backbone structure, which has neither antioxidant nor prooxidant action. In general, the more hydroxyl substitutions, the stronger the antioxidant and prooxidant activities. The flavonoids that contain multiple hydroxyl substitutions showed antiperoxyl radical activities several times stronger than Trolox, an alpha-to copherol analogue. The single hydroxyl substitution at position 5 provides no activity, whereas the di-OH substitution at 3' and 4' is particularly important to the peroxyl radical absorbing activity of a flavonoid. The conjugation between rings A and B does not affect the antioxidant activity but is very important for the copper-initiated prooxidant action of a flavonoid. The O-methylation of the hydroxyl substitutions inactivates both the antioxidant and the prooxidant activities of the flavonoids. PMID:9119242

Cao, G; Sofic, E; Prior, R L

1997-01-01

23

Structure-Activity Relationship for Thiirane-Based Gelatinase Inhibitors  

PubMed Central

An extensive structure-activity relationship study with the template of 2-(4-phenoxyphenylsulfonylmethyl)thiirane (1), a potent and highly selective inhibitor for human gelatinases, is reported herein. Syntheses of 65 new analogs, each in multistep processes, allowed for exploration of key structural components of the molecular template. This study reveals that the presence of the sulfonylmethylthiirane and the phenoxyphenyl group were important for gelatinase inhibition. However, para- and some meta-substitutions of the terminal phenyl ring enhanced inhibitory activity, and led to improve metabolic stability. This agrees with the result from metabolism studies with compound 1 that the primary route of biotransformation is oxidation, mainly at the para position of the phenyl ring and alpha position of the sulfonyl group in the aliphatic side chain.

Lee, Mijoon; Ikejiri, Masahiro; Klimpel, Dennis; Toth, Marta; Espahbodi, Mana; Hesek, Dusan; Forbes, Christopher; Kumarasiri, Malika; Noll, Bruce C.; Chang, Mayland; Mobashery, Shahriar

2012-01-01

24

Triptolide: structural modifications, structure-activity relationships, bioactivities, clinical development and mechanisms.  

PubMed

Triptolide, a principal bioactive ingredient of Tripterygium wilfordii Hook F, has attracted extensive exploration due to its unique structure of a diterpenoid triepoxide and multiple biological activities. This review will focus on the structural modifications, structure-activity relationships, pharmacology, and clinical development of triptolide in the last forty years. PMID:22270059

Zhou, Zhao-Li; Yang, Ya-Xi; Ding, Jian; Li, Yuan-Chao; Miao, Ze-Hong

2012-01-23

25

Structure-activity relationship studies of pyrrolone antimalarial agents.  

PubMed

Previously reported pyrrolones, such as TDR32570, exhibited potential as antimalarial agents; however, while these compounds have potent antimalarial activity, they suffer from poor aqueous solubility and metabolic instability. Here, further structure-activity relationship studies are described that aimed to solve the developability issues associated with this series of compounds. In particular, further modifications to the lead pyrrolone, involving replacement of a phenyl ring with a piperidine and removal of a potentially metabolically labile ester by a scaffold hop, gave rise to derivatives with improved in vitro antimalarial activities against Plasmodium falciparum K1, a chloroquine- and pyrimethamine-resistant parasite strain, with some derivatives exhibiting good selectivity for parasite over mammalian (L6) cells. Three representative compounds were selected for evaluation in a rodent model of malaria infection, and the best compound showed improved ability to decrease parasitaemia and a slight increase in survival. PMID:23918316

Murugesan, Dinakaran; Kaiser, Marcel; White, Karen L; Norval, Suzanne; Riley, Jennifer; Wyatt, Paul G; Charman, Susan A; Read, Kevin D; Yeates, Clive; Gilbert, Ian H

2013-08-05

26

Discovery and Structure-Activity Relationships of Pyrrolone Antimalarials  

PubMed Central

In the pursuit of new antimalarial leads, a phenotypic screening of various commercially sourced compound libraries was undertaken by the World Health Organisation Programme for Research and Training in Tropical Diseases (WHO-TDR). We report here the detailed characterization of one of the hits from this process, TDR32750 (8a), which showed potent activity against Plasmodium falciparum K1 (EC50 ? 9 nM), good selectivity (>2000-fold) compared to a mammalian cell line (L6), and significant activity against a rodent model of malaria when administered intraperitoneally. Structure–activity relationship studies have indicated ways in which the molecule could be optimized. This compound represents an exciting start point for a drug discovery program for the development of a novel antimalarial.

2013-01-01

27

Structure activity relationships: their function in biological prediction  

SciTech Connect

Quantitative structure activity relationships provide a means of ranking or predicting biological effects based on chemical structure. For each compound used to formulate a structure activity model two kinds of quantitative information are required: (1) biological activity and (2) molecular properties. Molecular properties are of three types: (1) molecular shape, (2) physiochemical parameters, and (3) abstract quantitations of molecular structure. Currently the two best descriptors are the hydrophobic parameter, log 1-octanol/water partition coefficient (log P), and the /sup 1/X/sup v/(one-chi-v) molecular connectivity index. Biological responses can be divided into three main categories: (1) non-specific effects due to membrane perturbation, (2) non-specific effects due to interaction with functional groups of proteins, and (3) specific effects due to interaction with receptors. Twenty-six synthetic fossil fuel-related nitrogen-containing aromatic compounds were examined to determine the quantitative correlation between log P and /sup 1/X/sup v/ and population growth impairment of Tetrahymena pyriformis. Nitro-containing compounds are the most active, followed by amino-containing compounds and azaarenes. Within each analog series activity increases with alkyl substitution and ring addition. The planar model log BR = 0.5564 log P + 0.3000 /sup 1/X/sup v/ -2.0138 was determined using mono-nitrogen substituted compounds. Attempts to extrapolate this model to dinitrogen-containing molecules were, for the most part, unsuccessful because of a change in mode of action from membrane perturbation to uncoupling of oxidative phosphoralation.

Schultz, T.W.

1982-01-01

28

Quantitative structure-activity relationships (QSAR) and molecular modelling in cancer research  

Microsoft Academic Search

Summary The methods of quantitative structure-activity relationships and molecular modelling that have developed during the last 25 years are nowadays widely applied to describe the relationships between chemical structures of molecules and their biological activities in a quantitative manner. In cancer research also, many attempts have been made to understand structure-activity relationships and to design new antitumor drugs on a

Hugo Kubinyi

1990-01-01

29

The structure?activity relationship in herbicidal monosubstituted sulfonylureas  

SciTech Connect

The herbicide sulfonylurea (SU) belongs to one of the most important class of herbicides worldwide. It is well known for its ecofriendly, extreme low toxicity towards mammals and ultralow dosage application. The original inventor, G Levitt, set out structure-activity relationship (SAR) guidelines for SU structural design to attain superhigh bioactivity. A new approach to SU molecular design has been developed. After the analysis of scores of SU products by X-ray diffraction methodology and after greenhouse herbicidal screening of 900 novel SU structures synthesized in the authors laboratory, it was found that several SU structures containing a monosubstituted pyrimidine moiety retain excellent herbicidal characteristics, which has led to partial revision of the Levitt guidelines. Among the novel SU molecules, monosulfuron and monosulfuron-ester have been developed into two new herbicides that have been officially approved for field application and applied in millet and wheat fields in China. A systematic structural study of the new substrate-target complex and the relative mode of action in comparison with conventional SU has been carried out. A new mode of action has been postulated.

Li, Zheng-Ming; Ma, Yi; Guddat, Luke; Cheng, Pei-Quan; Wang, Jian-Guo; Pang, Siew S; Dong, Yu-Hui; Lai, Cheng-Ming; Wang, Ling-Xiu; Jia, Guo-Feng; Li, Yong-Hong; Wang, Su-Hua; Liu, Jie; Zhao, Wei-Guang; Wang, Bao-Lei (Nankai); (Queens); (Chinese Aca. Sci.)

2012-05-24

30

Antioxidant activity of eugenol: a structure-activity relationship study.  

PubMed

Eugenol (4-allyl-2-methoxyphenol), a major phenolic component from clove oil (Eugenia caryophyllata), has several biological activities. To estimate the capacity of eugenol to act as an antioxidant, the following were studied: 1,1-diphenyl-2-picryl-hydrazyl-, 2,2'-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid)-, and N,N-dimethyl-p-phenylenediamine-scavenging activity; total antioxidant activity; and ability to reduce ferric ions and cupric ions. Eugenol inhibited 96.7% (r(2)=0.9319) lipid peroxidation of a linoleic acid emulsion at a 15-?g/mL concentration. Butylated hydroxyanisole, butylated hydroxytoluene, ?-tocopherol, and Trolox(®) displayed 95.4% (r(2)=0.8482), 99.7% (r(2)=0.7798), 84.6% (r(2)=0.9272), and 95.6% (r(2)=0.8511) inhibition of peroxidation, respectively, at the 15-?g/mL concentration. According to the results of this study, eugenol had the most powerful antioxidant activity and radical-scavenging activity. This study should prompt further studies of the antioxidant properties of eugenol. PMID:21554120

Gülçin, ?lhami

2011-05-09

31

Structure-activity relationship of cytoplasmic 5'-nucleotidase substrate sites.  

PubMed Central

Various 5'-nucleotidases (EC 3.1.3.5) exist in vertebrate tissues. The sequence and cDNA cloning of the membrane-bound ecto-5'-nucleotidase (e-N) and one of the cytosolic isoenzymes, IMP-preferring (c-N-II), but not the cytosolic AMP-preferring form (c-N-I), have been reported. While c-N-II has a broad tissue distribution, c-N-I is found only in vertebrate heart. The published data on substrate specificity involve mainly the naturally occurring nucleoside monophosphates, without a systematic structure-activity relationship study. In the present study we have used a series of AMP and IMP analogues to examine the structure-activity relationship for c-N-I and c-N-II in detail. The rank order of activity of the test compounds differed substantially between c-N-I and c-N-II. c-N-I and c-N-II varied with respect to the following interactions with substrate: (1) hydrogen-bond formation with the substituent in the 6-position of the purine ring (a donor-type with c-N-I and an acceptor-type with c-N-II); and (2) hydrophobic attraction of the 6-position unsubstituted purine ring (more pronounced with c-N-I than with c-N-II). No better substrate than 5'-AMP was found for c-N-I. We propose that c-N-I functions as an AMP-binding protein in the myocardial cell with an important role during ischaemic ATP breakdown when AMP accumulates rapidly.

Skladanowski, A C; Hoffmann, C; Krass, J; Jastorff, B; Makarewicz, W

1996-01-01

32

Structure-activity relationship of cyanine tau aggregation inhibitors  

PubMed Central

A structure-activity relationship for symmetrical cyanine inhibitors of human tau aggregation was elaborated using a filter trap assay. Antagonist activity depended on cyanine heterocycle, polymethine bridge length, and the nature of meso- and N-substituents. One potent member of the series, 3,3’-diethyl-9-methylthiacarbocyanine iodide (compound 11), retained submicromolar potency and had calculated physical properties consistent with blood-brain barrier and cell membrane penetration. Exposure of organotypic slices prepared from JNPL3 transgenic mice (which express human tau harboring the aggregation prone P301L tauopathy mutation) to compound 11 for one week revealed a biphasic dose response relationship. Low nanomolar concentrations decreased insoluble tau aggregates to half those observed in slices treated with vehicle alone. In contrast, high concentrations (?300 nM) augmented tau aggregation and produced abnormalities in tissue tubulin levels. These data suggest that certain symmetrical carbocyanine dyes can modulate tau aggregation in the slice biological model at concentrations well below those associated with toxicity.

Chang, Edward; Congdon, Erin E.; Honson, Nicolette S.; Duff, Karen E.; Kuret, Jeff

2009-01-01

33

Interpretable correlation descriptors for quantitative structure-activity relationships  

PubMed Central

Background The topological maximum cross correlation (TMACC) descriptors are alignment-independent 2D descriptors for the derivation of QSARs. TMACC descriptors are generated using atomic properties determined by molecular topology. Previous validation (J Chem Inf Model 2007, 47: 626-634) of the TMACC descriptor suggests it is competitive with the current state of the art. Results Here, we illustrate the interpretability of the TMACC descriptors, through the analysis of the QSARs of inhibitors of angiotensin converting enzyme (ACE) and dihydrofolate reductase (DHFR). In the case of the ACE inhibitors, the TMACC interpretation shows features specific to C-domain inhibition, which have not been explicitly identified in previous QSAR studies. Conclusions The TMACC interpretation can provide new insight into the structure-activity relationships studied. Freely available, open source software for generating the TMACC descriptors can be downloaded from http://comp.chem.nottingham.ac.uk.

2009-01-01

34

TMACC: interpretable correlation descriptors for quantitative structure-activity relationships.  

PubMed

Highly predictive topological maximum cross correlation (TMACC) descriptors for the derivation of quantitative structure-activity relationships (QSARs) are presented, based on the widely used autocorrelation method. They require neither the calculation of three-dimensional conformations nor an alignment of structures. We have validated the TMACC descriptors across eight literature data sets, ranging in size from 66 to 361 molecules. In combination with partial least-squares regression, they perform competitively with a current state-of-the-art 2D QSAR methodology, hologram QSAR (HQSAR), yielding larger leave-one-out cross-validated coefficient of determination values (LOO q2) for five data sets. Like HQSAR, these descriptors are also interpretable but do not require hashing. The interpretation both enables the automated extraction of SARs and can give a description in qualitative agreement with more time-consuming 3D and 4D QSAR methods. Open source software for generating the TMACC descriptors is freely available from our Web site. PMID:17381177

Melville, James L; Hirst, Jonathan D

35

Pearson versus Spearman Kendall's Tau Correlation Analysis on StructureActivity Relationships of Biologic Active Compounds  

Microsoft Academic Search

Abstract Asample,of sixty-seven pyrimidine derivatives with inhibitory activity on E. coli dihydrofolate reductase (DHFR) was ,studied by the ,use of molecular descriptors family on structure-activity relationships. Starting from the results obtained by applying ,of MDF-SAR methodology ,on pyrimidine ,derivatives and from the assumption ,that the measured activity (compounds’ inhibitory activity) of a ,biologically active compounds ,is a semi-quantitative outcome (can

Sorana-daniela Bolboac?; Lorentz Jäntschi

36

Structure-activity relationship of nerve-highlighting fluorophores.  

PubMed

Nerve damage is a major morbidity associated with numerous surgical interventions. Yet, nerve visualization continues to challenge even the most experienced surgeons. A nerve-specific fluorescent contrast agent, especially one with near-infrared (NIR) absorption and emission, would be of immediate benefit to patients and surgeons. Currently, there are only three classes of small molecule organic fluorophores that penetrate the blood nerve barrier and bind to nerve tissue when administered systemically. Of these three classes, the distyrylbenzenes (DSBs) are particularly attractive for further study. Although not presently in the NIR range, DSB fluorophores highlight all nerve tissue in mice, rats, and pigs after intravenous administration. The purpose of the current study was to define the pharmacophore responsible for nerve-specific uptake and retention, which would enable future molecules to be optimized for NIR optical properties. Structural analogs of the DSB class of small molecules were synthesized using combinatorial solid phase synthesis and commercially available building blocks, which yielded more than 200 unique DSB fluorophores. The nerve-specific properties of all DSB analogs were quantified using an ex vivo nerve-specific fluorescence assay on pig and human sciatic nerve. Results were used to perform quantitative structure-activity relationship (QSAR) modeling and to define the nerve-specific pharmacophore. All DSB analogs with positive ex vivo fluorescence were tested for in vivo nerve specificity in mice to assess the effect of biodistribution and clearance on nerve fluorescence signal. Two new DSB fluorophores with the highest nerve to muscle ratio were tested in pigs to confirm scalability. PMID:24039960

Gibbs, Summer L; Xie, Yang; Goodwill, Haley L; Nasr, Khaled A; Ashitate, Yoshitomo; Madigan, Victoria J; Siclovan, Tiberiu M; Zavodszky, Maria; Tan Hehir, Cristina A; Frangioni, John V

2013-09-09

37

Structure activity relationship of synaptic and junctional neurotransmission.  

PubMed

Chemical neurotransmission may include transmission to local or remote sites. Locally, contact between 'bare' portions of the bulbous nerve terminal termed a varicosity and the effector cell may be in the form of either synapse or non-synaptic contact. Traditionally, all local transmissions between nerves and effector cells are considered synaptic in nature. This is particularly true for communication between neurons. However, communication between nerves and other effectors such as smooth muscles has been described as nonsynaptic or junctional in nature. Nonsynaptic neurotransmission is now also increasingly recognized in the CNS. This review focuses on the relationship between structure and function that orchestrate synaptic and junctional neurotransmissions. A synapse is a specialized focal contact between the presynaptic active zone capable of ultrafast release of soluble transmitters and the postsynaptic density that cluster ionotropic receptors. The presynaptic and the postsynaptic areas are separated by the 'closed' synaptic cavity. The physiological hallmark of the synapse is ultrafast postsynaptic potentials lasting milliseconds. In contrast, junctions are juxtapositions of nerve terminals and the effector cells without clear synaptic specializations and the junctional space is 'open' to the extracellular space. Based on the nature of the transmitters, postjunctional receptors and their separation from the release sites, the junctions can be divided into 'close' and 'wide' junctions. Functionally, the 'close' and the 'wide' junctions can be distinguished by postjunctional potentials lasting ~1s and tens of seconds, respectively. Both synaptic and junctional communications are common between neurons; however, junctional transmission is the rule at many neuro-non-neural effectors. PMID:23535140

Goyal, Raj K; Chaudhury, Arun

2013-03-25

38

Application of machine learning approaches on quantitative structure activity relationships  

Microsoft Academic Search

Machine Learning techniques are successfully applied to establish quantitative relations between chemical structure and biological activity (QSAR), i.e. classify compounds as active or inactive with respect to a specific target biological system. This paper presents a comparison of artificial neural networks (ANN), support vector machines (SVM), and decision trees (DT) in an effort to identify potentiators of metabotropic glutamate receptor

Mariusz Butkiewicz; Ralf Mueller; Danilo Selic; Eric Dawson; Jens Meiler

2009-01-01

39

Initial Insights into Structure-Activity Relationships of Avian Defensins*  

PubMed Central

Numerous ?-defensins have been identified in birds, and the potential use of these peptides as alternatives to antibiotics has been proposed, in particular to fight antibiotic-resistant and zoonotic bacterial species. Little is known about the mechanism of antibacterial activity of avian ?-defensins, and this study was carried out to obtain initial insights into the involvement of structural features or specific residues in the antimicrobial activity of chicken AvBD2. Chicken AvBD2 and its enantiomeric counterpart were chemically synthesized. Peptide elongation and oxidative folding were both optimized. The similar antimicrobial activity measured for both l- and d-proteins clearly indicates that there is no chiral partner. Therefore, the bacterial membrane is in all likelihood the primary target. Moreover, this work indicates that the three-dimensional fold is required for an optimal antimicrobial activity, in particular for Gram-positive bacterial strains. The three-dimensional NMR structure of chicken AvBD2 defensin displays the structural three-stranded antiparallel ?-sheet characteristic of ?-defensins. The surface of the molecule does not display any amphipathic character. In light of this new structure and of the king penguin AvBD103b defensin structure, the consensus sequence of the avian ?-defensin family was analyzed. Well conserved residues were highlighted, and the potential strategic role of the lysine 31 residue of AvBD2 was emphasized. The synthetic AvBD2-K31A variant displayed substantial N-terminal structural modifications and a dramatic decrease in activity. Taken together, these results demonstrate the structural as well as the functional role of the critical lysine 31 residue in antimicrobial activity.

Derache, Chrystelle; Meudal, Herve; Aucagne, Vincent; Mark, Kevin J.; Cadene, Martine; Delmas, Agnes F.; Lalmanach, Anne-Christine; Landon, Celine

2012-01-01

40

Antioxidant, prooxidant and cytotoxic activity of hydroxylated resveratrol analogues: structure–activity relationship  

Microsoft Academic Search

Resveratrol (trans-3,4?,5-trihydroxystilbene), a naturally occurring hydroxystilbene, is considered an essential antioxidative constituent of red wine possessing chemopreventive properties. However, resveratrol and even more its metabolite piceatannol were reported to have also cytostatic activities. In order to find out whether this is related to antioxidative properties of those compounds, we synthesized five other polyhydroxylated resveratrol analogues and studied structure–activity relationships between

Marek Murias; Walter Jäger; Norbert Handler; Thomas Erker; Zsuzsanna Horvath; Thomas Szekeres; Hans Nohl; Lars Gille

2005-01-01

41

COMPUTER-ASSISTED STUDIES OF MOLECULAR STRUCTURE-BIOLOGICAL ACTIVITY RELATIONSHIPS  

EPA Science Inventory

Computer-assisted methods can be used to investigate the relationships between the molecular structures of compounds and their biological activity. A number of approaches have been reported in the literature, including correlations of activity with substituent constants, conforma...

42

Studies on the structure-activity relationship of bicifadine analogs as monoamine transporter inhibitors.  

PubMed

Compounds with various activities and selectivities were discovered through structure-activity relationship studies of bicifadine analogs as monoamine transporter inhibitors. The norepinephrine-selective 2-thienyl compound S-6j was efficacious in a rodent pain model. PMID:18539031

Zhang, Mingzhu; Jovic, Florence; Vickers, Troy; Dyck, Brian; Tamiya, Junko; Grey, Jonathan; Tran, Joe A; Fleck, Beth A; Pick, Rebecca; Foster, Alan C; Chen, Chen

2008-05-23

43

Studies on the structure–activity relationship of bicifadine analogs as monoamine transporter inhibitors  

Microsoft Academic Search

Compounds with various activities and selectivities were discovered through structure–activity relationship studies of bicifadine analogs as monoamine transporter inhibitors. The norepinephrine-selective 2-thienyl compound S-6j was efficacious in a rodent pain model.

Mingzhu Zhang; Florence Jovic; Troy Vickers; Brian Dyck; Junko Tamiya; Jonathan Grey; Joe A. Tran; Beth A. Fleck; Rebecca Pick; Alan C. Foster; Chen Chen

2008-01-01

44

Structure-activity relationships of polybiguanides with activity against human immunodeficiency virus type 1  

PubMed Central

Previous investigations showing that polydisperse biguanide (PDBG) molecules have activity against human immunodeficiency virus type 1 (HIV-1) also suggested a relationship between PDBG biologic activity and the lengths of hydrocarbon linkers surrounding the positively charged biguanide unit. To better define structure-activity relationships, PDBG molecules with select linker lengths were evaluated for cytotoxicity, anti-HIV-1 activity, and in vivo toxicity. Results of the in vitro experiments demonstrated that increases in linker length (and, therefore, increases in compound lipophilicity) were generally associated with increases in cytotoxicity and antiviral activity against HIV-1. However, a relationship between linker length asymmetry and in vitro therapeutic index (TI) suggested structural specificity in the mechanism of action against HIV-1. Polyethylene hexamethylene biguanide (PEHMB; biguanide units spaced between alternating ethylene and hexamethylene linkers) was found to have the highest in vitro TI (CC50/IC50) among the compounds examined. Recent improvements in PEHMB synthesis and purification have yielded preparations of PEHMB with in vitro TI values of 266 and 7000 against HIV-1 strains BaL and IIIB, respectively. The minimal toxicity of PEHMB relative to polyhexamethylene biguanide (PHMB; biguanide units alternating with hexamethylene linkers) in a murine model of cervicovaginal microbicide toxicity was consistent with considerable differences in cytotoxicity between PEHMB and PHMB observed during in vitro experiments. These structure-activity investigations increase our understanding of PDBG molecules as agents with activity against HIV-1 and provide the foundation for further preclinical studies of PEHMB and other biguanide-based compounds as antiviral and microbicidal agents.

Passic, Shendra R.; Ferguson, Mary Lee; Catalone, Bradley J.; Kish-Catalone, Tina; Kholodovych, Vladyslav; Zhu, Wei; Welsh, William; Rando, Robert; Howett, Mary K.; Wigdahl, Brian; Labib, Mohamed; Krebs, Fred C.

2013-01-01

45

Relationship between structure and anticoagulant activity of coumarin derivatives  

PubMed Central

Thirty-five coumarin derivatives have been examined for their anticoagulant activity in rabbits by determining the prothrombin time by a modification of Quick's onestage method, in order to find out the structural features eliciting the activity. The compounds include methoxylated dicoumarols, substituted 4-hydroxycoumarins, coumarins devoid of a 4-hydroxyl group, such as 3- and 4-phenylcoumarins and 4-methylcoumarins, and some complex coumarin derivatives having additional rings. The results show the complexity of the problem and the involvement of various factors. Among these the importance of molecular geometry is emphasized by the high activity of calophyllolide (31)* and a new synthetic compound, 4-methyl-2,5-dioxo-3-phenyl-2H,5H-pyrano[3,2-c][1]-benzopyran (30). The importance for the anticoagulant activity of a substituent in position 8 of the coumarin moiety, and the role of ability to ionize with regard to the vitamin-K-like property of some hydroxylated phenylcoumarins, are also indicated.

Arora, R. B.; Mathur, C. N.

1963-01-01

46

The Protein kinase inhibitor balanol: structure-activity relationships and structure-based computational studies.  

PubMed

Balanol, a fungal metabolite, is a potent ATP-competitive inhibitor of Protein Kinase C (PKC) and Protein Kinase A (PKA), important targets in oncology. Since its discovery in 1993, a number of studies have been performed in order to design selective and bioavailable balanol analogs. Several crystal structures of PKA in complex with balanol and a few analogs bound within the catalytic site have also been solved providing insight about the key interactions for binding. The PKA-balanol complex has also served as an interesting model system for structure-based ligand design and validation of a number of computational methodologies aimed at both understanding the physical basis for molecular recognition and addressing the important issue of protein flexibility in ligand binding. We provide an overview of the structure-activity relationships of balanol analogs and summarize the progress made in structural and computational studies involving balanol. PMID:18690827

Pande, Vineet; Ramos, Maria J; Gago, Federico

2008-08-01

47

Structure-activity relationship of aliphatic compounds for nematicidal activity against pine wood nematode (Bursaphelenchus xylophilus).  

PubMed

Nematicidal activity of aliphatic compounds was tested to determine a structure-activity relationship. There was a significant difference in nematicidal activity among functional groups. In a test with alkanols and 2E-alkenols, compounds with C(8)-C(11) chain length showed 100% nematicidal activity against pine wood nematode, Bursaphelenchus xylophilus , at 0.5 mg/mL concentration. C(6)-C(10) 2E-alkenals exhibited >95% nematicidal activity, but the other compounds with C(11)-C(14) chain length showed weak activity. Nematicidal activity of alkyl acetates with C(7)-C(11) chain length was strong. Compounds belonging to hydrocarbons, alkanals, and alkanoic acetates showed weak activity at 0.5 mg/mL concentration. Nematicidal activity of active compounds was determined at lower concentrations. At 0.25 mg/mL concentration, whole compounds except C(8) alkanol, C(8) 2E-alkenol, and C(7) alkanoic acid showed >80% nematicidal activity. C(9)-C(11) alkanols, C(10)-C(11) 2E-alkenols, C(8)-C(9) 2E-alkenals, and C(9)-C(10) alkanoic acids showed >80% nematicidal activity at 0.125 mg/mL concentration. Only C(11) alkanol exhibited strong nematicidal activity at 0.0625 mg/mL concentration, the lowest concentration that was tested. PMID:20055406

Seo, Seon-Mi; Kim, Junheon; Kim, Eunae; Park, Hye-Mi; Kim, Young-Joon; Park, Il-Kwon

2010-02-10

48

Antibacterial activity of xanthones from Garcinia mangostana (L.) and their structure-activity relationship studies.  

PubMed

Antibacterial activities of prenylated xanthones from Garcinia mangostana and their synthetic analogues were investigated, and their structure-activity relationships have been studied. ?-Mangostin has shown antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA), methicillin sensitive Staphylococcus aureus (MSSA), vancomycin-resistant Enterococcus (VRE) and vancomycin-sensitive Enterococcus (VSE) strains at MICs 3.13, 6.25, 6.25 and 6.25 µg mL(-1), respectively. In these experiments, gentamicin was used as the positive control. Further, some analogues of ?-mangostin and ?-mangostin were synthesised and their activity was tested against MRSA and VRE strains. The analysis of the bioassay results above indicated that, the combination of C-6 and C-3 hydroxyl groups along with the prenyl side chain at C-2 in the 1,3,6,7-tetraoxygenated xanthones from G. mangostana is essential to have a high antibacterial activity. PMID:22494050

Dharmaratne, H R W; Sakagami, Yoshikazu; Piyasena, K G P; Thevanesam, Vasanthi

2012-04-11

49

Quantitative structure–activity relationship (QSAR) approach for the selection of chelating mineral collectors  

Microsoft Academic Search

Quantitative structure–activity\\/property relationship (QSAR\\/QSPR) studies are mathematical quantification of relations between structure and activity or property. These are extensively used in pharmaceutical and agricultural chemistry for screening potential compounds for specific biological activity and also in environmental toxicology. The linear or nonlinear regression models that establish a relation between the structure and the activity\\/property are then used to predict the

R. Natarajan; I. Nirdosh

2008-01-01

50

Structure-Activity Relationship for Thiohydantoin Androgen Receptor Antagonists for Castration-Resistant Prostate Cancer (CRPC)  

PubMed Central

A structure-activity relationship study was carried out on a series of thiohydantoins and their analogues 14 which led to the discovery of 92 (MDV3100) as the clinical candidate for the treatment of hormone refractory prostate cancer.

Jung, Michael E.; Ouk, Samedy; Yoo, Dongwon; Sawyers, Charles L.; Chen, Charlie; Tran, Chris; Wongvipat, John

2011-01-01

51

Quantitative Structure--Activity Relationship Modeling of Rat Acute Toxicity by Oral Exposure  

EPA Science Inventory

Background: Few Quantitative Structure-Activity Relationship (QSAR) studies have successfully modeled large, diverse rodent toxicity endpoints. Objective: In this study, a combinatorial QSAR approach has been employed for the creation of robust and predictive models of acute toxi...

52

SIMPLIFYING COMPLEX QSAR'S (QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIPS) IN TOXICITY STUDIES WITH MULTIVARIATE STATISTICS  

EPA Science Inventory

During the past several decades many quantitative structure-activity relationships (QSAR's) have been derived from relatively small data sets of chemicals in a homologous series and selected empirical observations. An alternative approach is to analyze large data sets consisting ...

53

Proceedings of the Third International Workshop on Quantitative Structure-Activity Relationships in Environmental Toxicology.  

National Technical Information Service (NTIS)

The 3rd International Workshop on Quantitative Structure-Activity Relationships (QSAR) in Environmental Toxicology (QSAR-88) was organized to facilitate the exchange of ideas between experts in different areas working in QSAR. Invited participants were se...

J. E. Turner M. W. England N. J. Kwaak T. W. Schultz

1988-01-01

54

Simplifying Complex QSAR's (Quantitative Structure-Activity Relationships) in Toxicity Studies with Multivariate Statistics,  

National Technical Information Service (NTIS)

During the past several decades many quantitative structure-activity relationships (QSAR's) have been derived from relatively small data sets of chemicals in a homologous series and selected empirical observations. An alternative approach is to analyze la...

G. J. Niemi J. M. McKim

1988-01-01

55

DETERMINING THE STRUCTURE-ACTIVITY RELATIONSHIPS OF AMINOBIPHENYL AND BENZIDINE ANALOGS  

EPA Science Inventory

Determining the structure-activity relationships of aminobiphenyl and benzidine analogues Benzidine is a confirmed human carcinogen causing bladder and other types of cancer in humans and animals. Many of the benzidine and related aminobiphenyl compounds are mutagenic in t...

56

Probing structure-antifouling activity relationships of polyacrylamides and polyacrylates.  

PubMed

We have synthesized two different polyacrylamide polymers with amide groups (polySBAA and polyHEAA) and two corresponding polyacrylate polymers without amide groups (polySBMA and polyHEA), with particular attention to the evaluation of the effect of amide group on the hydration and antifouling ability of these systems using both computational and experimental approaches. The influence of polymer architectures of brushes, hydrogels, and nanogels, prepared by different polymerization methods, on antifouling performance is also studied. SPR and ELISA data reveal that all polymers exhibit excellent antifouling ability to repel proteins from undiluted human blood serum/plasma, and such antifouling ability can be further enhanced by presenting amide groups in polySBAA and polyHEAA as compared to polySBMA and polyHEA. The antifouling performance is positively correlated with the hydration properties. Simulations confirm that four polymers indeed have different hydration characteristics, while all presenting a strong hydration overall. Integration of amide group with pendant hydroxyl or sulfobetaine group in polymer backbones is found to increase their surface hydration of polymer chains and thus to improve their antifouling ability. Importantly, we present a proof-of-concept experiment to synthesize polySBAA nanogels, which show a switchable property between antifouling and pH-responsive functions driven by acid-base conditions, while still maintaining high stability in undiluted fetal bovine serum and minimal toxicity to cultured cells. This work provides important structural insights into how very subtle structural changes in polymers can yield great improvement in biological activity, specifically the inclusion of amide group in polymer backbone/sidechain enables to obtain antifouling materials with better performance for biomedical applications. PMID:23562049

Zhao, Chao; Zhao, Jun; Li, Xiaosi; Wu, Jiang; Chen, Shenfu; Chen, Qiang; Wang, Qiuming; Gong, Xiong; Li, Lingyan; Zheng, Jie

2013-04-02

57

Structure-activity relationship analysis of curcumin analogues on anti-influenza virus activity.  

PubMed

Curcumin (Cur) is a commonly used colouring agent and spice in food. Previously, we reported that Cur inhibits type A influenza virus (IAV) infection by interfering with viral haemagglutination (HA) activity. To search for a stable Cur analogue with potent anti-IAV activity and to investigate the structure contributing to its anti-IAV activity, a comparative analysis of structural and functional analogues of Cur, such as tetrahydrocurcumin (THC) and petasiphenol (Pet), was performed. The result of time-of-drug addition tests indicated that these curcuminoids were able to inhibit IAV production in cell cultures. Noticeably, Pet and THC inhibit IAV to a lesser extent than Cur, which is in line with their effect on reducing plaque formation when IAV was treated with Cur analogues before infection. Unexpectedly, both THC and Pet did not harbour any HA inhibitory effect. It should be noted that the structure of Pet and THC differs from Cur with respect to the number of double bonds present in the central seven-carbon chain, and structure modelling of Cur analogues indicates that the conformations of THC and Pet are distinct from that of Cur. Moreover, simulation docking of Cur with the HA structure revealed that Cur binds to the region constituting sialic acid anchoring residues, supporting the results obtained by the inhibition of HA activity assay. Collectively, structure-activity relationship analyses indicate that the presence of the double bonds in the central seven-carbon chain enhanced the Cur -dependent anti-IAV activity and also that Cur might interfere with IAV entry by its interaction with the receptor binding region of viral HA protein. PMID:24034558

Ou, Jun-Lin; Mizushina, Yoshiyuki; Wang, Sheng-Yang; Chuang, Duen-Yau; Nadar, Muthukumar; Hsu, Wei-Li

2013-09-23

58

Development of Computational Tools for Use in Quantitative Structure-Activity and Structure-Property Relationships  

NASA Astrophysics Data System (ADS)

Computational tools are developed to relate theoretical aspects of molecular structure to experimental chemical behavior. The assumption that a causal relationship exists between molecular structure and chemical behavior is the fundamental premise that underlies the fields of quantitative structure-activity relationships (QSAR) and quantitative structure-property relationships (QSPR). Generation of a QSAR or QSPR involves the characterization of chemical structure in terms of numerical indices, and the development of mathematical models that correlate these indices with biological activities or physicochemical properties. Tools are developed in this thesis for use at three important stages of this process. A fast quantum mechanical molecular modeling technique based on a modified extended Huckel approach is developed for placing molecules in realistic energy-minimized conformations. The extended Huckel neglect-of-differential-overlap (EHNDO) method utilizes a one-electron approximation, semiempirical parameterization, and an efficient BFGS geometry optimization. The calculated molecular geometries from EHNDO are as accurate as those produced by the two-electron AM1 method, and the EHNDO geometry optimization is approximately three times faster. A new empirical method for calculating atomic charges is developed to characterize electronic structure. These charges are used in combination with the concepts of induction and resonance to arrive at an empirical model for pK _ a estimation in organic acids and bases. The PKACHG method generates partial atomic charges that yield accurate predictions of electric dipole moment, and the pK_ a model is accurate over wide ranges of acidity and basicity. Finally, nonlinear mathematical modeling techniques are investigated as a means of generating QSARs and QSPRs that contain stronger connections between calculated structure and experimental chemical behavior. A computational neural network program, QNET, is developed and outfitted with an efficient BFGS optimization for network training. A quadratic fitting routine, QUADFIT, is proposed as a fast alternative to neural networks. Both QNET and QUADFIT utilize external cross-validation during model development to prevent experimental data from being overfit. In a QSAR study of amine toxicity, QNET significantly outperforms conventional linear regression, and both QNET and QUADFIT yield post-model predictions that are considerably more accurate than those of linear regression.

Dixon, Steven L.

59

Structure–radical scavenging activity relationships of phenolic compounds from traditional Chinese medicinal plants  

Microsoft Academic Search

Traditional Chinese medicinal plants associated with anticancer contain a wide variety of natural phenolic compounds with various structural features and possessing widely differing antioxidant activity. The structure–radical scavenging activity relationships of a large number of representative phenolic compounds (e.g., flavanols, flavonols, chalcones, flavones, flavanones, isoflavones, tannins, stilbenes, curcuminoids, phenolic acids, coumarins, lignans, and quinones) identified in the traditional Chinese medicinal

Yi-Zhong Cai; Mei Sun; Jie Xing; Qiong Luo; Harold Corke

2006-01-01

60

Flavanones in Citrus fruit: Structure–antioxidant activity relationships  

Microsoft Academic Search

Epidemiological surveys have shown an inverse relationship between the intake of fruit and the incidence of coronary heart disease and some type of cancer. Data found in the literature regarding the flavonoids in general while this study focuses on flavanones, a subclass of flavonoids which occurs in Citrus fruit. The aim of this work is to elucidate the antioxidant or

Danila Di Majo; Marco Giammanco; Maurizio La Guardia; Elisa Tripoli; Santo Giammanco; Enrico Finotti

2005-01-01

61

THE USE OF STRUCTURE-ACTIVITY RELATIONSHIPS IN INTEGRATING THE CHEMISTRY AND TOXICOLOGY OF ENDOCRINE DISRUPTING CHEMICALS  

EPA Science Inventory

Structure activity relationships (SARs) are based on the principle that structurally similar chemicals should have similar biological activity. SARs relate specifically-defined toxicological activity of chemicals to their molecular structure and physico-chemical properties. To de...

62

Thyroid hormone uptake by hepatocytes: structure-activity relationships of phenylanthranilic acids with inhibitory activity.  

PubMed

The synthesis of a series of mono- and disubstituted N-phenylanthranilic acids is described. Substituents on the phenyl ring include Cl, CN, OH, CF3, Br, I, CH3, OCH3, and OCF2CF2H. These compounds have been tested for their inhibitory effect on triiodothyronine (T3) uptake by H4 hepatocytes. The nonsteroidal antiinflammatory drugs flufenamic acid, mefenamic acid, and meclofenamic acid and the structurally related compounds 2,3-dimethyldiphenylamine and diclofenac were also tested. The most potent compounds were found to be, in order of decreasing activity, meclofenamic acid (2,6-Cl2,3-CH3), flufenamic acid (3-CF3), mefenamic acid (2,3-(CH3)2), and the compounds with 3,5-Cl2 and 3-OCF2CF2H substituents. The least potent compounds had 3-CN and 3-OH substituents. An analysis of quantitative structure-activity relationships (QSAR) for the series of phenylanthranilic acids showed that the inhibition of T3 uptake is highly dependent on the hydrophobicity of the compound. The relationship between uptake inhibition and the calculated octanol-water partition coefficient (clogP) was found to be parabolic, with optimum inhibitory activity found when the clogP of the phenylanthranilic acid was 5.7. It was also found that the 1-carboxylic acid group of the phenylanthranilic acids was not a prerequisite for uptake inhibition to occur, but its removal or alteration resulted in reduced inhibition. PMID:8487264

Chalmers, D K; Scholz, G H; Topliss, D J; Kolliniatis, E; Munro, S L; Craik, D J; Iskander, M N; Stockigt, J R

1993-04-30

63

Structure-Activity Relationships and Immunochemical Studies on Cobrotoxin.  

National Technical Information Service (NTIS)

The status of free amino groups in cobrotoxin was studied by stepwise modification with trinitrobenzene sulfonate. Lys-27 was selectively modified without altering the activity of cobrotoxin. However, complete loss of the activity was observed when Lys-27...

C. Yang

1971-01-01

64

ESTIMATION OF ELECTRON AFFINITY BASED ON STRUCTURE ACTIVITY RELATIONSHIPS  

EPA Science Inventory

Electron affinity for a wide range of organic molecules was calculated from molecular structure using the chemical reactivity models developed in SPARC. hese models are based on fundamental chemical structure theory applied to the prediction of chemical reactivities for organic m...

65

Novel glitazones: Design, synthesis, glucose uptake and structure–activity relationships  

Microsoft Academic Search

Glitazones are known to exhibit antihyperglycemic activity by decreasing peripheral insulin resistance. In the present study, we have designed some novel glitazones based on the structure–activity relationships as possible PPAR-? agonists. The manually designed glitazones were synthesized by using the appropriate synthetic schemes and screened for their in vitro antihyperglycemic activity by estimating glucose uptake by rat hemi-diaphragm, both in

B. R. Prashantha Kumar; M. J. Nanjan

2010-01-01

66

Multi-assay-based structure-activity relationship models: improving structure-activity relationship models by incorporating activity information from related targets.  

PubMed

Structure-activity relationship (SAR) models are used to inform and to guide the iterative optimization of chemical leads, and they play a fundamental role in modern drug discovery. In this paper, we present a new class of methods for building SAR models, referred to as multi-assay based, that utilize activity information from different targets. These methods first identify a set of targets that are related to the target under consideration, and then they employ various machine learning techniques that utilize activity information from these targets in order to build the desired SAR model. We developed different methods for identifying the set of related targets, which take into account the primary sequence of the targets or the structure of their ligands, and we also developed different machine learning techniques that were derived by using principles of semi-supervised learning, multi-task learning, and classifier ensembles. The comprehensive evaluation of these methods shows that they lead to considerable improvements over the standard SAR models that are based only on the ligands of the target under consideration. On a set of 117 protein targets, obtained from PubChem, these multi-assay-based methods achieve a receiver-operating characteristic score that is, on the average, 7.0 -7.2% higher than that achieved by the standard SAR models. Moreover, on a set of targets belonging to six protein families, the multi-assay-based methods outperform chemogenomics-based approaches by 4.33%. PMID:19842624

Ning, Xia; Rangwala, Huzefa; Karypis, George

2009-11-01

67

Discovery and structure-activity relationship studies of indole derivatives as liver X receptor (LXR) agonists.  

PubMed

A structurally novel liver X receptor (LXR) agonist (1) was identified from internal compound collection utilizing the combination of structure-based virtual screening and high-throughput gene profiling. Compound 1 increased ABCA1 gene expression by eightfold and SREBP1c by threefold in differentiated THP-1 macrophage cell lines. Confirmation of its agonistic activity against LXR was obtained in the co-factor recruitment and reporter transactivation assays. Structure-activity relationship studies on compound 1 are described. PMID:17416521

Bakir, Farid; Kher, Sunil; Pannala, Madhavi; Wilson, Norma; Nguyen, Trang; Sircar, Ila; Takedomi, Kei; Fukushima, Chiaki; Zapf, James; Xu, Kui; Zhang, Shao-Hui; Liu, Juping; Morera, Lisa; Schneider, Lisa; Sakurai, Naoki; Jack, Rick; Cheng, Jie-Fei

2007-03-27

68

Synthesis and structure-activity relationships of second-generation hydroxamate botulinum neurotoxin A protease inhibitors.  

PubMed

Botulinum neurotoxins are the most toxic proteins currently known. Based on a recently identified potent lead structure, 2,4-dichlorocinnamic acid hydroxamate, herein we report on the structure-activity relationship of a series of hydroxamate BoNT/A inhibitors. Among them, 2-bromo-4-chlorocinnamic acid hydroxamate, 2-methyl-4-chlorocinnamic acid hydroxamate, and 2-trifluoromethyl-4-chlorocinnamic acid hydroxamate displayed comparable inhibitory activity to that of the lead structure. PMID:17951059

Capková, Katerina; Yoneda, Yoshiyuki; Dickerson, Tobin J; Janda, Kim D

2007-10-09

69

Prediction of the relationship between the structural features of andrographolide derivatives and ?-glucosidase inhibitory activity: a quantitative structure-activity relationship (QSAR) study.  

PubMed

In order to predict the structural features responsible for ?-glucosidase inhibitory activity, a quantitative structure-activity relationship (QSAR) analysis was performed on a series of andrographolide derivatives. To determine the quantitative relationship for the statistically significant models in terms of r (>0.8), F (99%) and Q(2) (>0.71) values were selected. The promising results we obtained could be used to predict the structural requirements for the inhibition of ?-glucosidase activity. The models developed included: subdivided surface area, adjacency, surface volume and shape, molecular orbital package (MOPAC) and partial charge descriptors and showed a high correlation with the inhibitory activity. The descriptors used revealed that a van der Waals (vdW) surface with significant polar volume is favourable to the activity. The positive effect of the shape descriptors; PM3-LUMO and vsurf_wp7 and the negative effect of GCUT_PEOE_2 indicated that the active site may contain some nucleophilic positions that could interact with the ligand and the hydrogen acceptor and/or donor groups for hydrogen bonding with inhibitors. PMID:21171896

Moorthy, N S Hari Narayana; Ramos, Maria J; Fernandes, Pedro A

2010-12-20

70

Structure-activity relationship of dermorphin on gastric secretion.  

PubMed

The amphibian skin heptapeptide dermorphin (DM) administered intracerebroventricularly to rats significantly reduces gastric secretion. Dermorphin and 19 DM homologs and analogs were tested for their effect on gastric volume, pH, H+ ion concentration, and gastric acid output. DM, DM N-terminal pentapeptide and tetrapeptide amides, [D-Met2]DM, [Sar4]DM, [Trp5]DM, [Phe5]DM, [Gly7]DM, [Ser(Bzl)7]DM, and deamidated-DM significantly (P less than 0.01) reduced gastric acid output 2 h after injection. These data provide evidence for the following conclusions on the effect of DM on gastric secretion: ability to inhibit gastric secretion depends on the presence of the D-isomer of Ala at position 2, since [L-Ala2]DM is inactive; the shortest sequence with significant bioactivity is DM N-terminal tetrapeptide amide; the single replacement of amino acid residues in DM elicits a wide range of activities, varying from full biological activity of [Gly7]DM to those analogs with a complete lack of activity, such as [Pro4]DM and [Gly6]DM; and 4) coupling of protective groups to amino and hydroxyl groups of DM results in a significant loss of activity. PMID:3569127

Guglietta, A; Irons, B J; Lazarus, L H; Melchiorri, P

1987-05-01

71

Quantitative StructureActivity Relationship of Multidrug Resistance Reversal Agents  

Microsoft Academic Search

SUMMARY Multidrug resistance (MDR) is one of the major obstacles to long term successful cancer chemotherapy. The use of MDR reversal (MDRR) agents is a promising approach to overcome the undesired MDR phenotype. To design more effective MDRR agents that are urgently needed for clinical use, a data set of 609 diverse compounds tested for MDRR activity against P388\\/ADR-resistant cell

GILLES KLOPMAN; LEMING M. SHI; AVNER RAMU

1997-01-01

72

Structure-activity relationships of fluorinated lysophosphatidic acid analogues.  

PubMed

Lysophosphatidic acid (LPA, 1- or 2-acyl-sn-glycerol 3-phosphate) displays an intriguing cell biology that is mediated via interactions with seven-transmembrane G-protein-coupled receptors (GPCRs) and the nuclear hormone receptor PPARgamma. To identify receptor-selective LPA analogues, we describe a series of fluorinated LPA analogues in which either the sn-1 or sn-2 hydroxyl group was replaced by a fluoro or fluoromethyl substituent. We also describe stabilized phosphonate analogues in which the bridging oxygen of the monophosphate was replaced by an alpha-monofluoromethylene (-CHF-) or alpha-difluoromethylene (-CF(2)-) moiety. The sn-2- and sn-1-fluoro-LPA analogues were unable to undergo acyl migration, effectively "freezing" them in the sn-1-O-acyl or sn-2-O-acyl forms, respectively. We first tested these LPA analogues on insect Sf9 cells induced to express human LPA(1), LPA(2), and LPA(3) receptors. While none of the analogues were found to be more potent than 1-oleoyl-LPA at LPA(1) and LPA(2), several LPA analogues were potent LPA(3)-selective agonists. In contrast, 1-oleoyl-LPA had similar activity at all three receptors. The alpha-fluoromethylene phosphonate analogue 15 activated calcium release in LPA(3)-transfected insect Sf9 cells at a concentration 100-fold lower than that of 1-oleoyl-LPA. This activation was enantioselective, with the (2S)-enantiomer showing 1000-fold more activity than the (2R)-enantiomer. Similar results were found for calcium release in HT-29 and OVCAR8 cells. Analogue 15 was also more effective than 1-oleoyl-LPA in activating MAPK and AKT in cells expressing high levels of LPA(3). The alpha-fluoromethylene phosphonate moiety greatly increased the half-life of 15 in cell culture. Thus, alpha-fluoromethylene LPA analogues are unique new phosphatase-resistant ligands that provide enantiospecific and receptor-specific biological readouts. PMID:15857137

Xu, Yong; Aoki, Junken; Shimizu, Kumiko; Umezu-Goto, Makiko; Hama, Kotaro; Takanezawa, Yasukazu; Yu, Shuangxing; Mills, Gordon B; Arai, Hiroyuki; Qian, Lian; Prestwich, Glenn D

2005-05-01

73

Isolation, structures, and structure - cytotoxic activity relationships of withanolides and physalins from Physalis angulata.  

PubMed

Phytochemical investigation of Physalis angulata was initiated following primary biological screening. Fractionation of CHCl3 and n-BuOH solubles of the MeOH extract from the whole plant was guided by in vitro cytotoxic activity assay using cultured HONE-1 and NUGC cells and led to the isolation of seven new withanolides, withangulatins B-H (1-7), and a new minor physalin, physalin W (8), along with 14 known compounds, including physaprun A, withaphysanolide, dihydrowithanolide E, physanolide A, withaphysalin A, and physalins B, D, F, G, I, J, T, U, and V. New compounds (1-8) were fully characterized by a combination of spectroscopic methods (1D and 2D NMR and MS) and the relative stereochemical assignments based on NOESY correlations and analysis of coupling constants. Biological evaluation of these compounds against a panel of human cancer cell lines showed broad cytotoxic activity. Withangulatin B (1) and physalins D (10) and F (11) displayed potent cytotoxic activity against a panel of human cancer cell lines with EC50 values ranging from 0.2 to 1.6 microg/mL. Structure-activity relationship analysis indicated that withanolides and physalins with 4beta-hydroxy-2-en-1-one and 5beta,6beta-epoxy moieties are potential cytotoxic agents. PMID:17580910

Damu, Amooru G; Kuo, Ping-Chung; Su, Chung-Ren; Kuo, Tsung-Hsiao; Chen, Tzu-Hsuan; Bastow, Kenneth F; Lee, Kuo-Hsiung; Wu, Tian-Shung

2007-06-20

74

Ecotoxicological Quantitative Structure–Activity Relationships for Pharmaceuticals  

Microsoft Academic Search

This paper examined active pharmaceutical ingredients (APIs) acute ecotoxicological modes of action (MOA). It was concluded\\u000a that the vast majority of APIs acute MOA was non-specific narcosis as; 85% out of 59 APIs had an excess toxicity ratio <7;\\u000a 70% of the APIs ecotoxicity was overestimated based on a narcotic model; and the majority of APIs Log EC50-Log K\\u000a ow regression

Hans Sanderson; Marianne Thomsen

2007-01-01

75

Visual and computational analysis of structure–activity relationships in high-throughput screening data  

Microsoft Academic Search

Novel analytic methods are required to assimilate the large volumes of structural and bioassay data generated by combinatorial chemistry and high-throughput screening programmes in the pharmaceutical and agrochemical industries. Recent work in visualisation and data mining has been used to develop structure–activity relationships from such chemical-biological datasets.

Peter Gedeck; Peter Willett

2001-01-01

76

STRUCTURE-ACTIVITY RELATIONSHIPS FOR SCREENING ORGANIC CHEMICALS FOR POTENTIAL ECOTOXICITY EFFECTS  

EPA Science Inventory

The paper presents structure-activity relationships (QSAR) for estimating the bioconcentration factor and acute toxicity of some classes of industrial chemicals using only the n-octanol/water partition coefficient (Log P) which is derived from chemical structure. The bioconcentra...

77

Hot and Spicy versus Cool and Minty as an Example of Organic Structure-Activity Relationships  

NASA Astrophysics Data System (ADS)

There are two classes of substances that activate neural receptors that are involved in temperature perception. Structures of substances found in spices and food that we normally associate with "hot" (or spicy) and "cool" (or minty) flavors are presented and discussed. Functional group similarities within the two groups provide an interesting example of the relationship between molecular structure and molecular function in organic chemistry.

Kimbrough, Doris R.

1997-07-01

78

A review on structure-activity relationship of dietary polyphenols inhibiting ?-amylase  

Microsoft Academic Search

The inhibitory effects of dietary polyphenols against ?-amylase have attracted great interest among researchers. The aim of this review is to give an overview of the research reports on the structure- activity relationship of polyphenols inhibiting ?-amylase. The molecular structures influence the inhibition are the following: 1) The hydroxylation of flavonoids improved the inhibitory effect on ?-amylase; 2) Presence of

Guoyin Kai; Xiaoling Ni; Xiaoqing Chen; Jianbo Xiao

2011-01-01

79

Ecotoxicological quantitative structure-activity relationships for pharmaceuticals.  

PubMed

This paper examined active pharmaceutical ingredients (APIs) acute ecotoxicological modes of action (MOA). It was concluded that the vast majority of APIs acute MOA was non-specific narcosis as; 85% out of 59 APIs had an excess toxicity ratio <7; 70% of the APIs ecotoxicity was overestimated based on a narcotic model; and the majority of APIs Log EC(50)-Log K (ow )regression slopes (-0.49 to -0.86) were within the range of the universal narcosis slopes. However, hydrophobicity is likely not the proper descriptor for assessment of pharmacodynamic APIs chronic ecotoxicity, to asses this accurately new experimental methods need development. PMID:17701090

Sanderson, Hans; Thomsen, Marianne

2007-08-16

80

Structure-activity relationships in human toll-like receptor 7-active imidazoquinoline analogues.  

PubMed

Engagement of toll-like receptors serve to link innate immune responses with adaptive immunity and can be exploited as powerful vaccine adjuvants for eliciting both primary and anamnestic immune responses. TLR7 agonists are highly immunostimulatory without inducing dominant proinflammatory cytokine responses. A structure-activity study was conducted on the TLR7-agonistic imidazoquinolines, starting with 1-(4-amino-2-((ethylamino)methyl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol as a lead. Modifications of the secondary amine of the C2 ethylaminomethylene side chain are poorly tolerated. The 4-amino group must be retained for activity. Replacement of the imidazole ring of the scaffold with triazole or cyclic urea led to complete loss of activity. A systematic exploration of N(1)-benzyl-C2-alkyl substituents showed a very distinct relationship between alkyl length and TLR7-agonistic potency with the optimal compound bearing a C2-n-butyl group. Transposition of the N(1) and C2 substituents led to the identification of an extremely active TLR7-agonistic compound with an EC(50) value of 8.6 nM. The relative potencies in human TLR7-based primary reporter gene assays were paralleled by interferon-alpha induction activities in whole human blood models. PMID:20481492

Shukla, Nikunj M; Malladi, Subbalakshmi S; Mutz, Cole A; Balakrishna, Rajalakshmi; David, Sunil A

2010-06-10

81

Structure-Activity Relationships in Human Toll-like Receptor 7-Active Imidazoquinoline Analogues  

PubMed Central

Engagement of toll-like receptors serve to link innate immune responses with adaptive immunity and can be exploited as powerful vaccine adjuvants for eliciting both primary and anamnestic immune responses. TLR7 agonists are highly immunostimulatory without inducing dominant proinflammatory cytokine responses. A structure-activity study was conducted on the TLR7-agonistic imidazoquinolines, starting with 1-(4-amino-2-((ethylamino)methyl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol as a lead. Modifications of the secondary amine of the C2 ethylaminomethylene sidechain are poorly tolerated. The 4-amino group must be retained for activity. Replacement of the imidazole ring of the scaffold with triazole or cyclic urea led to complete loss of activity. A systematic exploration of N1-benzyl-C2-alkyl substituents showed a very distinct relationship between alkyl length and TLR7-agonistic potency with the optimal compound bearing a C2-n-butyl group. Transposition of the N1 and C2 substituents led to the identification of an extremely active TLR7-agonistic compound with an EC50 value of 8.6 nM. The relative potencies in human TLR7-based primary reporter gene assays were paralleled by interferon-? induction activities in whole human blood models.

Shukla, Nikunj M.; Malladi, Subbalakshmi S.; Mutz, Cole A.; Balakrishna, Rajalakshmi; David, Sunil A.

2010-01-01

82

Molecular structure and radiative efficiency of fluorinated ethers: A structure-activity relationship  

NASA Astrophysics Data System (ADS)

Fluorinated ethers are receiving attention as possible replacements for ozone-depleting substances. Accurate knowledge of their radiative forcing is required to assess the contribution of these compounds to climate change. Radiative efficiency is a metric used to determine the potential of long-lived greenhouse gases to impact climate. A structure-activity relationship (SAR) was derived that can estimate the majority of radiative efficiencies of fluorinated ether compounds within 25% of the published experimentally determined values. The SAR allows prediction of radiative efficiency solely from molecular structure and was developed from 154 calculated and 11 experimentally measured infrared spectra for fluorinated ethers. Stretching vibrations for C-F bonds adjacent to an ether oxygen absorb at lower frequencies than those which are further removed from the ether moiety, which typically gives rise to a higher radiative efficiency. Molecular structure plays an important role in determining the radiative efficiency of fluorinated ethers. The SAR developed herein could be used in the design of new fluorinated ethers that have minimal climate impacts.

Young, Cora J.; Hurley, Michael D.; Wallington, Timothy J.; Mabury, Scott A.

2008-12-01

83

Structure-activity relationships of unsaturated analogues of valproic acid.  

PubMed

The principal metabolite of valproic acid (VPA), 2-ene VPA, appears to share most of VPA's pharmacological and therapeutic properties while lacking its hepatotoxicity and teratogenicity, thus making it a useful lead compound for the development of safer antiepileptic drugs. Analogues of 2-ene VPA were evaluated for anticonvulsant activity in mice using the subcutaneous pentylenetetrazole test. Cyclooctylideneacetic acid exhibited a potency markedly exceeding that of VPA itself with only modest levels of sedation. Potency, as either ED50 or brain concentration, was highly correlated (r > 0.85) with volume and lipophilicity rather than with one of the shape parameters calculated by molecular modeling techniques, arguing against the existence of a specific receptor site. Instead, a role for the plasma membrane in mediating the anticonvulsant effect is suggested. PMID:7650693

Palaty, J; Abbott, F S

1995-08-18

84

Structural Relationships between Social Activities and Longitudinal Trajectories of Depression among Older Adults  

ERIC Educational Resources Information Center

|Purpose: This study examines the structural relationships between social activities and trajectories of late-life depression. Design and Methods: Latent class analysis was used with a nationally representative sample of older adults (N = 5,294) from the Longitudinal Study on Aging II to classify patterns of social activities. A latent growth…

Hong, Song-Iee; Hasche, Leslie; Bowland, Sharon

2009-01-01

85

Structural Relationships between Social Activities and Longitudinal Trajectories of Depression among Older Adults  

ERIC Educational Resources Information Center

Purpose: This study examines the structural relationships between social activities and trajectories of late-life depression. Design and Methods: Latent class analysis was used with a nationally representative sample of older adults (N = 5,294) from the Longitudinal Study on Aging II to classify patterns of social activities. A latent growth curve…

Hong, Song-Iee; Hasche, Leslie; Bowland, Sharon

2009-01-01

86

Structure-activity relationship investigation of bis(2-chloroethyl)aminoethyl esters of some carboxylic acids.  

PubMed

A study of quantitative structure-activity relationships (QSAR) in a series of carboxylic acid bis(2-chloroethyl)aminoethyl esters with potential antitumor activity was carried out. The statistical-heuristic technique was applied to estimate the contributions of the structural features of the compounds to the probability of their activity in vivo against lymphoid leukemia L1210. The results obtained were compared with those of the pharmacological screening of the esters. Some assumptions are made concerning the difference in antileukemic activity of compounds based on the computed weights of their structural features. PMID:2395899

Pajeva, I; Manolov, I; Golovinsky, E V

1990-05-01

87

Synthesis and structure–activity relationships of sinenxan A derivatives as multidrug resistance reversal agents  

Microsoft Academic Search

Two types of sinenxan A derivatives with different side chains at C-5 were synthesized and evaluated for their in vitro multidrug resistant reversal activities. Several derivatives exhibited better activities than the positive control verapamil. The structure–activity relationships of these derivatives suggested that a carbonyl group at C-13 and the length of side chain at C-5 are important for the activity.

Meng Huang; Xin Zhao; Meng Zhang; Jun Gu; Xiaoguang Chen; Dali Yin

2010-01-01

88

Structure-activity relationships of novel neuritogenic steroid glycosides from the Okinawan starfish Linckia laevigata.  

PubMed

Six new steroid glycosides, linckosides F-K, and a related metabolite were isolated from the Okinawan blue starfish Linckia laevigata as mimics or enhancers of nerve growth factor (NGF). Their structures and stereochemistry were elucidated by spectroscopic methods and chemical derivatization. Structure-activity relationships suggest that both a carbon branch modified by a pentose at the side chain and 2'-O-methylxylopyranose at C-3 of the aglycon are important for neuritogenic activity. PMID:16524736

Han, Chunguang; Qi, Jianhua; Ojika, Makoto

2006-03-09

89

Dibasic inhibitors of human mast cell tryptase. Part 2: Structure–activity relationships and requirements for potent activity  

Microsoft Academic Search

Detailed structure–activity relationships (SARs) for a series of dibasic human tryptase inhibitors are presented. The structural requirements for potent inhibitory activity are remarkably broad with a range of core template modifications being well tolerated. Optimized inhibitors demonstrate potent anti-asthmatic activity in a sheep model of allergic asthma. APC-2059, a dibasic tryptase inhibitor with subnanomolar activity, has been advanced to phase

Kenneth D Rice; Vivian R Wang; Anthony R Gangloff; Elaine Y.-L Kuo; Jeffrey M Dener; William S Newcomb; Wendy B Young; Daun Putnam; Lynne Cregar; Martin Wong; Paul J Simpson

2000-01-01

90

Synthesis and structure-activity relationships of 3-hydrazono-1H-2-indolinones with antituberculosis activity.  

PubMed

A series of 3-[S-(4-substituted phenacyl)-4-substituted-isothiosemicarbazono]-1H-2-indolinones+ ++ 2a-h and 3-[(3,4-disubstituted-4-thiazolin-2-ylidene)hydrazono]-1H-2- indolinones 3a-f were synthesized. These new hydrazonoindolinone derivatives and 3-(4-substituted-thiosemicarbazono)-1H/1-acetyl-2-indolinones++ + 1a-g 3-[(2-substituted-4-thiazolidinon-2-ylidene)hydrazono]-1H-2- indolinones 4a-o, 3-[(2-substituted-4-carboxy/carbetoxy-5-methyl-4-thiazolin-2 -ylidene) hydrazono]-1H-2-indolinones 5a-e and 3-substituted-hydrazono-1H-2-indolinones 6a-o which had been previously reported were evaluated for antituberculosis activity against Mycobacterium tuberculosis H37Rv. These compounds exhibited varying degrees of inhibition in the in vitro primary screening that was conducted at 12 micrograms/ml against M. tuberculosis H37Rv in BACTEC 12B medium using the BACTEC 460 radiometric system. 2a, 2c, 2f-h, 3c and 3f demonstrating activity in the primary screen were re-tested at lower concentrations against M. tuberculosis H37Rv to determine the actual minimum inhibitory concentration (MIC) in CABTEC 460. The structure-activity relationships of the derivatives were investigated. PMID:9706377

Karah, N; Terzio?lu, N; Gürsoy, A

1998-07-01

91

Using Quantitative Structure–Activity Relationships (QSAR) to Predict Toxic Endpoints for Polycyclic Aromatic Hydrocarbons (PAH)  

Microsoft Academic Search

Quantitative structure–activity relationships (QSAR) offer a reliable, cost-effective alternative to the time, money, and animal lives necessary to determine chemical toxicity by traditional methods. Additionally, humans are exposed to tens of thousands of chemicals in their lifetimes, necessitating the determination of chemical toxicity and screening for those posing the greatest risk to human health. This study developed models to predict

Erica D. Bruce; Robin L. Autenrieth; Robert C. Burghardt; K. C. Donnelly; Thomas J. McDonald

2008-01-01

92

Proton dissociation is important to understanding structure–activity relationships of gallic acid antioxidants  

Microsoft Academic Search

Gallic acid derivatives (GADs) can efficiently scavenge free radicals, which is partially responsible for their neuroprotective effects. As GADs tend to deprotonate to give birth to GAD anions, which has big influence on the radical-scavenging behaviors of GADs, to understand the structure–activity relationships (SARs) of GAD antioxidants, the anions should be taken into consideration. In this paper, a combined density

Hong-Fang Ji; Hong-Yu Zhang; Liang Shen

2006-01-01

93

On the nature, evolution and future of quantitative structure-activity relationships (QSAR) in toxicology  

Microsoft Academic Search

The quantitative structure-activity relationship (QSAR) science agenda is being determined by its skeptics. Toxic substances control legislation over the past 30 years was born of a culture that tests animals and interprets the results of those tests in attempts to protect public health. Even with the current awareness that there are many more chemicals to assess than resources and test

G. D. Veith

2004-01-01

94

Quantitative structure-activity relationships and ecological risk assessment: an overview of predictive aquatic toxicology research  

Microsoft Academic Search

In the field of aquatic toxicology, quantitative structure-activity relationships (QSARs) have developed as scientifically credible tools for predicting the toxicity of chemicals when little or no empirical data are available. A fundamental understanding of toxicological principles has been considered an important component to the acceptance and application of QSAR approaches as biologically relevant in ecological risk assessments. As a consequence,

Steven P. Bradbury

1995-01-01

95

Application of Quantitative Structure–Activity Relationships for Assessing the Aquatic Toxicity of Phthalate Esters  

Microsoft Academic Search

Phthalate esters (PEs) are an important class of industrial chemicals for which an extensive aquatic toxicity database is available. The objectives of this study were to use these data to develop quantitative structure–activity relationships (QSARs) that describe aquatic toxicity for different freshwater and marine species, gain insights into toxicity mechanisms, and calculate PE water quality criteria using statistical extrapolation procedures.

Thomas F. Parkerton; Wolfgang J. Konkel

2000-01-01

96

STRUCTURE-ACTIVITY RELATIONSHIPS (SARS) AMONG MUTAGENS AND CARCINOGENS: A REVIEW  

EPA Science Inventory

The review is an introduction to methods for evaluating structure-activity relationships (SARs), and, in particular, to those methods that have been applied to study mutagenicity and carcinogenicity. A brief history and some background material on the earliest attempts to correla...

97

QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIPS FOR CHEMICAL REDUCTIONS OF ORGANIC CONTAMINANTS  

EPA Science Inventory

Sufficient kinetic data on abiotic reduction reactions involving organic contaminants are now available that quantitative structure-activity relationships (QSARs) for these reactions can be developed. Over 50 QSARs have been reported, most in just the last few years, and they ar...

98

The application of structure-activity relationships in human hazard assessment: a first approach  

Microsoft Academic Search

In this report an overview is given of structure-activity relationships\\u000a(SARs) described in literature that can be helpful for the daily human\\u000ahazard evaluation of chemicals. SARs describe the relation between\\u000amolecular structure and biological- or physical-chemical activity of the\\u000achemical. Chemicals that share structural features are presented that\\u000acan have an effect on the toxicological endpoints: irritation,\\u000asensitisation, neurotoxicity

Hulzebos EM; Janssen PAH; Maslankiewicz L; Meijerink MCM; Muller JJA; Pelgrom SMG; Verdam L; Vermeire TG

2007-01-01

99

A computational study of the structure-activity relationships of some p -hydroxybenzoic acid antioxidants  

Microsoft Academic Search

Equilibrium structures of all derivatized systems of p-hydroxybenzoic acid, 3,4-dihydroxybenzoic acid, 3-methoxy-4-hydroxybenzoic acid, and 3,5-dimethoxy-4-hydroxybenzoic acid\\u000a and calculated structural and energetic molecular descriptors were determined at the B3LYP\\/6-31+G(d) density functional theoretical\\u000a level in an attempt to study their structure-activity relationships (SAR). The theoretical antioxidant activity trend, derived\\u000a in terms of hydrogen-donating capacity against radicals in lipid systems, is in excellent

Anastasios P. Vafiadis; Evangelos G. Bakalbassis

2003-01-01

100

Structure–activity relationship between carboxylic acids and T cell cycle blockade  

Microsoft Academic Search

This study was designed to examine the potential structure–activity relationship between carboxylic acids, histone acetylation and T cell cycle blockade. Toward this goal a series of structural homologues of the short-chain carboxylic acid n-butyrate were studied for their ability to block the IL-2-stimulated proliferation of cloned CD4+ T cells. The carboxylic acids were also tested for their ability to inhibit

Kathleen M. Gilbert; Annick DeLoose; Jimmie L. Valentine; E. Kim Fifer

2006-01-01

101

Structure–activity relationship and biological property of cortistatins, anti-angiogenic spongean steroidal alkaloids  

Microsoft Academic Search

Previously, bioassay-guided separation led us to isolate eleven novel steroidal alkaloids named cortistatins from the marine sponge Corticium simplex. These cortistatins were classified into three types based on the chemical structure of the side chain part, that is, isoquinoline, N-methyl piperidine or 3-methylpyridine units. From the structure–activity relationship study, the isoquinoline unit in the side chain was found to be

Shunji Aoki; Yasuo Watanabe; Daiki Tanabe; Masayoshi Arai; Hideaki Suna; Katsushiro Miyamoto; Hiroshi Tsujibo; Kazutake Tsujikawa; Hiroshi Yamamoto; Motomasa Kobayashi

2007-01-01

102

Tumor specific cytotoxicity of ?-glucosylceramide: structure–cytotoxicity relationship and anti-tumor activity in vivo  

Microsoft Academic Search

This study describes the structure–cytotoxicity relationship of ?-glucosylceramide (?-GluCer) and its antitumor activity in\\u000a vivo. Unglycosylated ceramide had no selective cytotoxicity which demonstrated that the sugar moiety plays a critical role\\u000a for the expression of selective cytotoxicity by ?-GluCer. ?-Galactosylceramide also showed tumor specific cytotoxicity suggesting\\u000a that the chemical structure of sugar group is not a factor for the selective

Hirosuke Oku; Changchun Li; Masayuki Shimatani; Hironori Iwasaki; Takayoshi Toda; Takafumi Okabe; Hisami Watanabe

2009-01-01

103

Indolo[3,2-b]quinolines: Synthesis, Biological Evaluation and Structure Activity-Relationships  

PubMed Central

The tetracyclic indolo[3,2-b]quinoline ring system constitutes an important structural moiety in natural products exhibiting numerous biological activities. In particular, indolo [3, 2-b]quinoline, commonly known as linear quindo-line is of particular interest, because of its rigid structure and scope of derivatization. Although the core linear quindoline skeleton shows little or no activity in several biological systems, introduction of a methyl group on the N-5 atom leading to cryptolepine induces remarkable activity against a broad spectrum of biological targets. A number of analogs of quindoline and cryptolepine have been synthesized, incorporating various functional groups on the core quindoline skeleton leading to improved biological activities. In this review, we describe various synthetic methodologies leading to the quindoline scaffold, the biological activities and the structure activity relationships (SAR) of quindoline derivatives toward different disease states to give a better picture of the importance of this moiety in medicinal chemistry.

Kumar, Eyunni V.K. Suresh; Etukala, Jagan R.; Ablordeppey, Seth Y.

2013-01-01

104

Structure-activity relationships for saponins from Allium hirtifolium and Allium elburzense and their antispasmodic activity.  

PubMed

A phytochemical study of Allium hirtifolium Boiss flowers has led to the isolation of high amounts of six new furostanol and spirostanol saponins, named hirtifoliosides A1/A2 (1a/ 1b), B (2), C1/C2 ( 3a/ 3b), and D(4) along with three known spirostanol saponins, alliogenin 3- O-beta-D-glucopyranoside, gitogenin 3- O-beta-D-glucopyranosyl-(1-->4)- O-beta-D-glucopyranoside, and agapanthagenin 3- O-beta-D-glucopyranoside. High concentrations of the following known flavonol glycosides have been isolated from both flowers and bulbs: kaempferol 3- O-beta-D-rhamnopyranosyl-(1-->2)-glucopyranoside, kaempferol 3- O-beta-D-glucopyranosyl-(1-->4)-glucopyranoside, kaempferol 3-O-glucopyranoside, kaempferol 7-O-glucopyranoside. The isolated saponins along with the four saponins elburzensosides A1/A2 and C1/C2 and the sapogenin agapanthagenin, previously described from A. elburzense, have been subjected to biological assays for evaluating possible antispasmodic activity in the guinea-pig isolated ileum. The obtained results served as a basis for the establishment of structure-activity relationships within this class of antispasmodic agents. They highlight the positive effects of a hydroxyl group at position 5 and of a glucose unit at position 26 and demonstrate the detrimental effects of both a hydroxyl group at position 6 and of a glucose unit at position 3. Among the tested compounds, elburzensosides C1/C2 and agapanthagenin showed the highest activity in reducing induced contractions as measured by the reduction of histamine release by about 50 %. The observed effect therefore contributes to the explanation of the traditional use of onion and garlic in the treatment of disturbances of the gastrointestinal tract. PMID:16320201

Barile, Elisa; Capasso, Raffaele; Izzo, Angelo A; Lanzotti, Virginia; Sajjadi, S Ebrahim; Zolfaghari, Behzad

2005-11-01

105

Quantitative structure-activity relationships of antimicrobial fatty acids and derivatives against Staphylococcus aureus *  

PubMed Central

Fatty acids and derivatives (FADs) are resources for natural antimicrobials. In order to screen for additional potent antimicrobial agents, the antimicrobial activities of FADs against Staphylococcus aureus were examined using a microplate assay. Monoglycerides of fatty acids were the most potent class of fatty acids, among which monotridecanoin possessed the most potent antimicrobial activity. The conventional quantitative structure-activity relationship (QSAR) and comparative molecular field analysis (CoMFA) were performed to establish two statistically reliable models (conventional QSAR: R 2=0.942, Q 2 LOO=0.910; CoMFA: R 2=0.979, Q 2=0.588, respectively). Improved forecasting can be achieved by the combination of these two models that provide a good insight into the structure-activity relationships of the FADs and that may be useful to design new FADs as antimicrobial agents.

Zhang, Hui; Zhang, Lu; Peng, Li-juan; Dong, Xiao-wu; Wu, Di; Wu, Vivian Chi-Hua; Feng, Feng-qin

2012-01-01

106

Structure-activity relationship of citrus polymethoxylated flavones and their inhibitory effects on Aspergillus niger.  

PubMed

Citrus peels are rich in polymethoxylated flavones (PMFs) and are potential sources of natural preservatives. Six PMFs extracts, isolated and purified from the peels of three mandarins (Citrus reticulata) and three sweet oranges (Citrus sinensis), were identified and quantitated. Their inhibitory effects on Aspergillus niger were evaluated using a microbroth dilution assay. The Red tangerine variety exhibited the greatest antifungal activity (MIC = 0.2 mg/mL), while Jincheng showed the lowest activity (MIC = 1.8 mg/mL). An analysis of principal components was applied to the results in order to elucidate the structure-activity relationships of the citrus PMFs. The structure-activity relationship analysis revealed that, for good inhibitory effect, the 5-OH, 3-OCH?, and 8-OCH? functionalities were essential, while the presence of 3-OH and 3'-OCH? greatly reduced inhibition. The findings of this study provide important information for the exploitation and utilization of citrus PMFs as natural biopreservatives. PMID:22500738

Liu, Li; Xu, Xiaoyun; Cheng, Dan; Yao, Xiaolin; Pan, Siyi

2012-04-20

107

The sedative effect of inhaled terpinolene in mice and its structure-activity relationships.  

PubMed

Terpinolene is a cyclic monoterpene compound found in some Labiatae herbs. In our previous study, we evaluated the sedative effect of inhaled essential oils of Microtoena patchoulii leaves in mice and isolated terpinolene as an active ingredient. We investigated the structure-activity relationships of terpinolene to identify the structural part essential to its sedative effect. Comparison of terpinolene analog activities showed that a double bond in the side-chain or pi bonds in the six-membered ring play important roles in the sedative effect. In another experiment using olfactory impaired mice, we further revealed that inhaled terpinolene exerted the effect after nasal absorption into the body. PMID:23339024

Ito, Ken; Ito, Michiho

2013-01-22

108

Discovery and structure–activity relationships of novel sulfonamides as potent PTP1B inhibitors  

Microsoft Academic Search

A series of novel sulfonamides containing a single difluoromethylene-phosphonate group were discovered to be potent inhibitors of protein tyrosine phosphatase 1B. Structure–activity relationships around the scaffold were investigated, leading to the identification of compounds with IC50 or Ki values in the low nanomolar range. These sulfonamide-based inhibitors exhibit 100 and 30 times higher inhibitory activity than the corresponding tertiary amines

Christopher P. Holmes; Xianfeng Li; Yijun Pan; Caiding Xu; Ashok Bhandari; Claire M. Moody; Joy A. Miguel; Steven W. Ferla; M. Nuria De Francisco; Brian T. Frederick; Siqun Zhou; Natalie Macher; Larry Jang; Jennifer D. Irvine; J. Russell Grove

2005-01-01

109

Relationships between Structures of Hydroxyflavone Derivatives and their Anti-oxidative Activities  

Microsoft Academic Search

Primuletin, chrysin, and luteolin belong to hydroxyflavones. Although they have small differences in their hydroxyl groups, these make big differences in their biological activities. In order to elucidate relationships between structures of hydroxyflavones and their biological activities, we tested anti-oxidative effects of 20 hydroxyflavone derivatives belonged to flavonoids, which are well-known to possess anti- oxidative effects. 1,1-Diphenyl-2-picryl-hydrazyl (DPPH) radical scavenging

Younghee Park; Sunhee Lee; Yoongho Lim

2007-01-01

110

Structure–activity relationship analysis of antioxidant ability and neuroprotective effect of gallic acid derivatives  

Microsoft Academic Search

Gallic acid and its derivatives are a group of naturally occurring polyphenol antioxidants which have recently been shown to have potential healthy effects. In order to understand the relationship between the structures of gallic acid derivatives, their antioxidant activities, and neuroprotective effects, we examined their free radical scavenging effects in liposome and anti-apoptotic activities in human SH-SY5Y cell induced by

Zhongbing Lu; Guangjun Nie; Peter S. Belton; Huiru Tang; Baolu Zhao

2006-01-01

111

StructureActivity Relationships of Retinoids in Hamster Trachea! Organ Culture  

Microsoft Academic Search

Structure-activity relationships are summarized for 87 reti- noids, using reversal of keratinization in the hamster trachéal organ culture system to measure biological activity. Classes of compounds evaluated include all-frans-retinoic acid and its esters, ring-modified analogs of all-frans-retinoic acid and its esters, side-chain-modified analogs of all-frans-retinoic acid and its esters, analogs in which both ring and side chain have been modified,

Dianne L. Newton; William R. Henderson; Michael B. Sporn

112

Structure-antioxidant activity relationships of flavonoids: a re-examination.  

PubMed

The antioxidant and prooxidant activities of flavonoids belonging to several classes were studied to establish their structure-activity relationships against different oxidants. Special attention was paid to the flavonoids quercetin (flavone), taxifolin (flavanone) and catechin (flavanol), which possess different basic structures but the same hydroxylation pattern (3,5,7,3'4'-OH). It was found that these three flavonoids exhibited comparable antioxidant activities against different oxidants leading to the conclusion that the presence of ortho-catechol group (3',4'-OH) in the B-ring is determinant for a high antioxidant capacity. The flavone kaempferol (3,5,7,4'-OH), however, in spite of bearing no catechol group, also presents a high antioxidant activity against some oxidants. This fact can be attributed to the presence of both 2,3-double bond and the 3-hydroxyl group, meaning that the basic structure of flavonoids becomes important when the antioxidant activity of B-ring is small. PMID:12592674

Silva, M Manuela; Santos, Marta R; Caroço, Gonçalo; Rocha, Rui; Justino, Gonçalo; Mira, Lurdes

2002-11-01

113

Relationships between Brain Activation and Brain Structure in Normally Developing Children  

PubMed Central

Dynamic changes in brain structure, activation, and cognitive abilities co-occur during development, but little is known about how changes in brain structure relate to changes in cognitive function or brain activity. By using cortical pattern matching techniques to correlate cortical gray matter thickness and functional brain activity over the entire brain surface in 24 typically developing children, we integrated structural and functional magnetic resonance imaging data with cognitive test scores to identify correlates of mature performance during orthographic processing. Fast-naming individuals activated the right fronto-parietal attention network in response to novel fonts more than slow-naming individuals, and increased activation of this network was correlated with more mature brain morphology in the same fronto-parietal region. These relationships remained even after effects of age or general cognitive ability were statistically controlled. These results localized cortical regions where mature morphology corresponds to mature patterns of activation, and may suggest a role for experience in mediating brain structure–activation relationships.

Lu, Lisa H.; Dapretto, Mirella; O'Hare, Elizabeth D.; Kan, Eric; McCourt, Sarah T.; Thompson, Paul M.; Toga, Arthur W.; Bookheimer, Susan Y.

2009-01-01

114

Structure Modification and Functionality of Whey Proteins: Quantitative StructureActivity Relationship Approach  

Microsoft Academic Search

According to the original idea of quantitative structure-activity relation- ship, electric, hydrophobic, and structural parameters should be taken into con- sideration for elucidating functionality. Changes in these parameters are reflected in the property of protein solubility upon modification of whey proteins by heating. Although solubility is itself a functional property, it has been utilized to explain other functionalities of proteins.

S. Nakai; E. Li-chan

1985-01-01

115

Simple isatin derivatives as free radical scavengers: Synthesis, biological evaluation and structure-activity relationship  

PubMed Central

To develop more potent small molecules with enhanced free radical scavenger properties, a series of N-substituted isatin derivatives was synthesized, and the cytoprotective effect on the apoptosis of PC12 cells induced by H2O2 was screened. All these compounds were found to be active, and N-ethyl isatin was found with the most potent activity of 69.7% protective effect on PC12 cells. Structure-activity relationship analyses showed the bioactivity of N-alkyl isatins decline as the increasing of the chain of the alkyl group, furthermore odd-even effect was found in the activity, which is interesting for further investigation.

2011-01-01

116

Synthesis and structure-activity relationship analysis of caffeic acid amides as selective matrix metalloproteinase inhibitors.  

PubMed

Four series of acid amides were synthesized, and through measurement using a fluorogenic substrate assay with human recombinant MMP-1, MMP-2 and MMP-9, compound 3f showed considerable inhibitory activities against MMP-2, MMP-9 and the best selectivity over MMP-1. Preliminary structure-activity relationship analysis indicated that caffeic acid amides with electron-donating groups at para-position of amino phenyl group showed better inhibitory activities and selectivity than those with electron-withdrawing groups, and the presence of adjacent dihydroxy in the caffeoyl group was very important for the MMP-2 and MMP-9 inhibitory activities. PMID:23375794

Shi, Zhi-Hao; Li, Nian-Guang; Shi, Qian-Ping; Tang, Hao; Tang, Yu-Ping; Li, Wei; Yin, Lian; Yang, Jian-Ping; Duan, Jin-Ao

2013-01-16

117

Structure-function relationship of working memory activity with hippocampal and prefrontal cortex volumes.  

PubMed

A rapidly increasing number of studies are quantifying the system-level network architecture of the human brain based on structural-to-structural and functional-to-functional relationships. However, a largely unexplored area is the nature and existence of "cross-modal" structural-functional relationships, in which, for example, the volume (or other morphological property) of one brain region is related to the functional response to a given task either in that same brain region, or another brain region. The present study investigated whether the gray matter volume of a selected group of structures (superior, middle, and inferior frontal gyri, thalamus, and hippocampus) was correlated with the fMRI response to a working memory task, within a mask of regions previously identified as involved with working memory. The subjects included individuals with schizophrenia, their siblings, and healthy controls (n = 154 total). Using rigorous permutation testing to define the null distribution, we found that the volume of the superior and middle frontal gyri was correlated with working memory activity within clusters in the intraparietal sulcus (i.e., dorsal parietal cortex) and that the volume of the hippocampus was correlated with working memory activity within clusters in the dorsal anterior cingulate cortex and left inferior frontal gyrus. However, we did not find evidence that the identified structure-function relationships differed between subject groups. These results show that long-distance structural-functional relationships exist within the human brain. The study of such cross-modal relationships represents an additional approach for studying systems-level interregional brain networks. PMID:22362200

Harms, Michael P; Wang, Lei; Csernansky, John G; Barch, Deanna M

2012-02-24

118

Synthesis and structure-activity relationship of botryllamides that block the ABCG2 multidrug transporter.  

PubMed

In previous work, botryllamides discovered from the marine ascidian Botryllus tyreus were characterized as selective inhibitors of the ABCG2 multidrug transporter. However, the structural basis for this activity could not be established. In this study, botryllamide F, the core botryllamide structure, and botryllamide G, the most potent botryllamide ABCG2 inhibitor, were synthesized along with a series of structural variants for evaluation of structure-activity relationships. The biological activity of synthetic botryllamide analogs implied that the 2-methoxy-p-coumaric acid portion, and the degree of double bond conjugation within this group, were critical for inhibition of ABCG2. However, variations in the substituents on the two aryl groups did not appear to significantly impact the potency or degree of inhibition. PMID:20097565

Takada, Kentaro; Imamura, Nobutaka; Gustafson, Kirk R; Henrich, Curtis J

2010-01-11

119

Synthesis and Structure-Activity Relationship of Botryllamides that Block the ABCG2 Multidrug Transporter  

PubMed Central

In previous work, botryllamides discovered from the marine ascidian Botryllus tyreus were characterized as selective inhibitors of the ABCG2 multidrug transporter. However, the structural basis for this activity could not be established. In this study, botryllamide F, the core botryllamide structure, and botryllamide G, the most potent botryllamide ABCG2 inhibitor, were synthesized along with a series of structural variants for evaluation of structure–activity relationships. The biological activity of synthetic botryllamide analogs implied that the 2-methoxy-p-coumaric acid portion, and the degree of double bond conjugation within this group, were critical for inhibition of ABCG2. However, variations in the substituents on the two aryl groups did not appear to significantly impact the potency or degree of inhibition.

Takada, Kentaro; Imamura, Nobutaka; Gustafson, Kirk R.; Henrich, Curtis J.

2010-01-01

120

Inhibitors of the Interaction of Thyroid Hormone Receptor and Coactivators: Preliminary Structure-Activity Relationships  

PubMed Central

The modulation of gene regulation by blocking the interaction between the thyroid receptor (TR) and obligate coregulators (CoRs) has been reported recently with discovery of the lead compound 3-(dimethylamino)-1-(4-hexylphenyl)propan-1-one). Herein we report studies aimed at optimization of this initial hit to determine the basic parameters of the structure–activity relationships (SAR) and clarify the mechanism of action. These studies provided new insights, showing that activity and TR? isoform selectivity is highly correlated with the structural composition of these covalent inhibitors.

Arnold, Leggy A.; Kosinski, Aaron; Estebanez-Perpina, Eva; Guy, R. Kiplin

2008-01-01

121

Relationship between structure and antiproliferative activity of polymethoxyflavones towards HL60 cells.  

PubMed

As part of our continuing investigation of polymethoxyflavone (PMF) derivatives as potential anticancer substances, a series of PMF derivatives was synthesized. The synthesized compounds were evaluated for cytotoxicity against the promyelocytic leukemic HL60 cell line, and structure-activity relationship correlations were investigated along with previously isolated PMFs from the peel of king orange (Citrus nobilis). 7,3'-Dimethoxyflavone demonstrated the most potent activity among the synthetic PMFs. Consideration of correlation between the methoxylation pattern and antiproliferative activity revealed the importance of the 3'-methoxyl group and the higher degree of methoxylation on the A-ring moiety of PMFs. PMID:23225422

Kawaii, Satoru; Ikuina, Tomoyasu; Hikima, Takeshi; Tokiwano, Tetsuo; Yoshizawa, Yuko

2012-12-01

122

Structure-activity relationship study on benzoic acid part of diphenylamine-based retinoids.  

PubMed

Based on structure-activity relationship studies of the benzoic acid part of diphenylamine-based retinoids, the potent RXR agonist 4 was derivatized to obtain retinoid agonists, synergists, and an antagonist. Cinnamic acid derivatives 5 and phenylpropionic acid derivatives 6 showed retinoid agonistic and synergistic activities, respectively. The difference of the activities is considered to be due to differences in the flexibility of the carboxylic acid-containing substituent on the diphenylamine skeleton. Compound 7, bearing a methyl group at the meta position to the carboxyl group, was an antagonist, dose-dependently inhibiting HL-60 cell differentiation induced by 3.3 × 10(-10)M Am80. PMID:23217961

Ohta, Kiminori; Kawachi, Emiko; Shudo, Koichi; Kagechika, Hiroyuki

2012-11-15

123

3D-quantitative structure-activity relationship study of organophosphate compounds  

Microsoft Academic Search

The biological effects of most organophosphate compounds (OP) are arising by inhibition of the enzyme acetylcholinesterase\\u000a (AChE). The 3D-quantitative structure-activity relationship (3D-QSAR) on the acute toxicity to housefly (Musca nobulo L.) of 35 dialkyl phenyl phosphate compounds are studied by using comparative molecular field analysis (CoMFA) and comparative\\u000a molecular similarity index analysis (CoMSIA) methods, and the reaction mechanism between the

Jinsong Zhao; Bin Wang; Zhaoxia Dai; Xiaodong Wang; Lingren Kong; Liansheng Wang

2004-01-01

124

Structure-activity relationship for (+)-taxifolin isolated from silymarin as an inhibitor of amyloid ? aggregation.  

PubMed

Silymarin, the seed extract of Silybium marianum, has preventive effects against Alzheimer's disease-like pathogenesis in vivo. We isolated (+)-taxifolin (4) from silymarin as an inhibitor of aggregation of the 42-residue amyloid ?-protein. Structure-activity relationship studies revealed the 3',4'-dihydroxyl groups to be critical to the anti-aggregative ability, whereas the 7-hydroxyl group and the stereochemistry at positions 2 and 3 were not important. PMID:23649236

Sato, Mizuho; Murakami, Kazuma; Uno, Mayumi; Ikubo, Haruko; Nakagawa, Yu; Katayama, Sumie; Akagi, Ken-Ichi; Irie, Kazuhiro

2013-05-07

125

Quantitative structure activity relationship (QSAR) of N 6 -substituted adenosine receptor agonists as potential antihypertensive agents  

Microsoft Academic Search

Quantitative structure activity relationship studies are indubitably of great importance in modern chemistry. In pursuit of\\u000a better antihypertensive agents, QSAR studies were performed on a series of 48 N\\u000a 6-substituted adenosines analogs. The models were developed using multiple linear regression (MLR) and partial least square\\u000a (PLS) with many descriptors like electronic, topological, and lipophilic. QSAR models were evaluated for statistical

Sarvesh Paliwal; Sucheta Das; Divya Yadav; Manyata Saxena; Shailendra Paliwal

126

Three-dimensional quantitative structure activity relationships (3-D-QSAR) of antihyperglycemic agents  

Microsoft Academic Search

A three-dimensional quantitative structure activity relationship study (3-D-QSAR) was performed on a set of thiazolidinedione antihyperglycemic agents using the comparative molecular field analysis (CoMFA) method. The CoMFA models were derived from a training set of 53 compounds. Fifteen compounds, which were not used in model generation were used to validate the CoMFA models. All the compounds were superimposed to the

Santosh S Kulkarni; Lalji K Gediya; Vithal M Kulkarni

1999-01-01

127

Chemical Sensor Array Response Modeling Using Quantitative StructureActivity Relationships Technique  

Microsoft Academic Search

\\u000a We have developed a Quantitative Structure-Activity Relationships (QSAR) based approach to correlate the response of chemical\\u000a sensors in an array with molecular descriptors. A novel molecular descriptor set has been developed; this set combines descriptors\\u000a of sensing film-analyte interactions, representing sensor response, with a basic analyte descriptor set commonly used in QSAR\\u000a studies. The descriptors are obtained using a combination

Abhijit V. Shevade; Margaret A. Ryan; Margie L. Homer; Hanying Zhou; Allison M. Manfreda; Liana M. Lara; Shiao-Pin S. Yen; April D. Jewell; Kenneth S. Manatt; Adam K. Kisor

2009-01-01

128

Trainable structure-activity relationship model for virtual screening of CYP3A4 inhibition  

Microsoft Academic Search

A new structure–activity relationship model predicting the probability for a compound to inhibit human cytochrome P450 3A4\\u000a has been developed using data for >800 compounds from various literature sources and tested on PubChem screening data. Novel\\u000a GALAS (Global, Adjusted Locally According to Similarity) modeling methodology has been used, which is a combination of baseline\\u000a global QSAR model and local similarity

Justas Dapkunas; Andrius Sazonovas; Pranas Japertas

2010-01-01

129

Design, synthesis and structure–activity relationships of azole acids as novel, potent dual PPAR ?\\/? agonists  

Microsoft Academic Search

The design, synthesis and structure–activity relationships of a novel series of N-phenyl-substituted pyrrole, 1,2-pyrazole and 1,2,3-triazole acid analogs as PPAR ligands are outlined. The triazole acid analogs 3f and 4f were identified as potent dual PPAR?\\/? agonists both in binding and functional assays in vitro. The 3-oxybenzyl triazole acetic acid analog 3f showed excellent glucose and triglyceride lowering in diabetic

Hao Zhang; Denis E. Ryono; Pratik Devasthale; Wei Wang; Kevin O’Malley; Dennis Farrelly; Liqun Gu; Thomas Harrity; Michael Cap; Cuixia Chu; Kenneth Locke; Litao Zhang; Jonathan Lippy; Lori Kunselman; Nathan Morgan; Neil Flynn; Lisa Moore; Vinayak Hosagrahara; Lisa Zhang; Pathanjali Kadiyala; Carrie Xu; Arthur M. Doweyko; Aneka Bell; Chiehying Chang; Jodi Muckelbauer; Robert Zahler; Narayanan Hariharan; Peter T. W. Cheng

2009-01-01

130

Structure-activity relationships of ?s-casein peptides with multifunctional biological activities.  

PubMed

Multifunctional bioactive peptides have a wider role in modulating physiological functions and possess multiple biological activities. Peptides from bovine milk with sequences QKALNEINQF [p10] and TKKTKLTEEEKNRL [p14] from ?-S2 casein f (79-88) and ?-S2 casein f (148-161) were identified to be having multifunctional biological activities and were synthesized. These synthesized peptides show various biological activities like angiotensin-converting enzyme inhibition, prolyl endopeptidase inhibition, antioxidant, and antimicrobial activities. The mode of antimicrobial mechanism was studied and p10 shows depolarization of cell membrane, whereas p14 was found to display DNA-binding activity. Structural studies envisaged backbone flexibility, for differences in their mode of action. Peptide structure function studies were correlated to understand their multifunctional biological activity. PMID:23963991

Sistla, Srinivas

2013-08-21

131

HomoSAR: Bridging comparative protein modeling with quantitative structural activity relationship to design new peptides.  

PubMed

Peptides play significant roles in the biological world. To optimize activity for a specific therapeutic target, peptide library synthesis is inevitable; which is a time consuming and expensive. Computational approaches provide a promising way to simply elucidate the structural basis in the design of new peptides. Earlier, we proposed a novel methodology termed HomoSAR to gain insight into the structure activity relationships underlying peptides. Based on an integrated approach, HomoSAR uses the principles of homology modeling in conjunction with the quantitative structural activity relationship formalism to predict and design new peptide sequences with the optimum activity. In the present study, we establish that the HomoSAR methodology can be universally applied to all classes of peptides irrespective of sequence length by studying HomoSAR on three peptide datasets viz., angiotensin-converting enzyme inhibitory peptides, CAMEL-s antibiotic peptides, and hAmphiphysin-1 SH3 domain binding peptides, using a set of descriptors related to the hydrophobic, steric, and electronic properties of the 20 natural amino acids. Models generated for all three datasets have statistically significant correlation coefficients (r(2) ) and predictive r2 (rpred?2) and cross validated coefficient ( qLOO?2). The daintiness of this technique lies in its simplicity and ability to extract all the information contained in the peptides to elucidate the underlying structure activity relationships. The difficulties of correlating both sequence diversity and variation in length of the peptides with their biological activity can be addressed. The study has been able to identify the preferred or detrimental nature of amino acids at specific positions in the peptide sequences. © 2013 Wiley Periodicals, Inc. PMID:24105965

Borkar, Mahesh R; Pissurlenkar, Raghuvir R S; Coutinho, Evans C

2013-09-18

132

Structure-Activity Relationships of Synthetic Coumarins as HIV-1 Inhibitors  

PubMed Central

HIV/AIDS pandemics is a serious threat to health and development of mankind, and searching for effective anti-HIV agents remains actual. Considerable progress has been made in recent years in the field of drug development against HIV. A lot of structurally different coumarins were found to display potent anti-HIV activity. The current review demonstrates the variety of synthetic coumarins having unique mechanism of action referring to the different stages of HIV replication. Recent studies based on the account of various synthetic coumarins seem to indicate that some of them serve as potent non-nucleoside RT-inhibitors, another as inhibitors of HIV-integrase or HIV-protease. The merits of selecting potential anti-HIV agents to be used in rational combination drugs design and structure-activity relationships are discussed.The scientific community is looking actively for new drugs and combinations for treatment of HIV infection effective for first-line treatment, as well as against resistant mutants. The investigation on chemical anti-HIV agents gives hope and optimism about it. This review article describes recent progress in the discovery, structure modification, and structure-activity relationship studies of potent anti-HIV coumarin derivatives.

Kostova, I.; Raleva, S.; Genova, P.; Argirova, R.

2006-01-01

133

Structure-activity relationship study of trifluoromethylketones: inhibitors of insect juvenile hormone esterase.  

PubMed

The juvenile hormone esterase (JHE) regulates juvenile hormone titre in insect hemolymph during its larval development. It has been suggested that JHE could be targeted for use in insect control. This enzyme can also be considered as involved in the phenomenon of endocrine disruption by xenobiotics in beneficial insects. Consequently, there is a need to know the characteristics of the molecules able to act on the JHE. Trifluoromethylketones (TFKs) are the most potent JHE inhibitors found to date and different quantitative structure-activity relationships (QSARs) have been derived for this group of chemicals. In this context, a set of 181 TFKs (118 active and 63 inactive compounds), tested on Trichoplusia ni for their JHE inhibition activity and described by physico-chemical descriptors, was split into different training and test sets to derive structure-activity relationship (SAR) models from support vector classification (SVC). A SVC model including 88 descriptors and derived from a Gaussian kernel was selected for its predictive performances. Another model computed only with 13 descriptors was also selected due to its mechanistic interpretability. This study clearly illustrates the difficulty in capturing the essential structural characteristics of the TFKs explaining their JHE inhibitory activity. PMID:23721304

Doucet, J P; Doucet-Panaye, A; Devillers, J

2013-05-30

134

Stimulation of Orobanche ramosa seed germination by fusicoccin derivatives: a structure-activity relationship study.  

PubMed

A structure-activity relationship study was conducted assaying 25 natural analogues and derivatives of fusicoccin (FC), and cotylenol, the aglycone of cotylenins, for their ability to stimulate the seed germination of the parasitic species Orobanche ramosa. Some of the compounds tested proved to be highly active, being 8,9-isopropylidene of the corresponding FC aglycone and the dideacetyl derivative the most active FC derivatives. In both groups of glucosides and aglycones (including cotylenol), the most important structural feature to impart activity appears to be the presence of the primary hydroxy group at C-19. Furthermore, the functionalities and the conformation of the carbotricyclic ring proved to play a significant role. The dideacetyl derivative of FC, being easily and rapidly obtainable in high yield starting by FC, could be of interest for its practical application as a stimulant of Orobanche ramosa seed germination, inducing the "suicidal germination", an interesting approach for parasitic plant management. PMID:16310229

Evidente, Antonio; Andolfi, Anna; Fiore, Michele; Boari, Angela; Vurro, Maurizio

2005-11-28

135

Structure-activity relationship for the reactivators of acetylcholinesterase inhibited by nerve agent VX.  

PubMed

Nerve agents such as sarin, VX and tabun are organophosphorus compounds able to inhibit an enzyme acetylcholinesterase (AChE). AChE reactivators and anticholinergics are generally used as antidotes in the case of intoxication with these agents. None from the known AChE reactivators is able to reactivate AChE inhibited by all kinds of nerve agents. In this work, reactivation potency of seventeen structurally different AChE reactivators was tested in vitro and subsequently, relationship between their chemical structure and biological activity was outlined. VX was chosen as appropriate member of the nerve agent family. PMID:22779796

Kuca, Kamil; Musilek, Kamil; Jun, Daniel; Karasova, Jana; Soukup, Ondrej; Pejchal, Jaroslav; Hrabinova, Martina

2013-08-01

136

Structure-activity relationship study of selective benzimidazole-based inhibitors of Cryptosporidium parvum IMPDH.  

PubMed

Cryptosporidium parasites are important waterborne pathogens of both humans and animals. The Cryptosporidium parvum and Cryptosporidium hominis genomes indicate that the only route to guanine nucleotides is via inosine 5'-monophosphate dehydrogenase (IMPDH). Thus the inhibition of the parasite IMPDH presents a potential strategy for treating Cryptosporidium infections. A selective benzimidazole-based inhibitor of C. parvum IMPDH (CpIMPDH) was previously identified in a high throughput screen. Here we report a structure-activity relationship study of benzimidazole-based compounds that resulted in potent and selective inhibitors of CpIMPDH. Several compounds display potent antiparasitic activity in vitro. PMID:22310229

Kirubakaran, Sivapriya; Gorla, Suresh Kumar; Sharling, Lisa; Zhang, Minjia; Liu, Xiaoping; Ray, Soumya S; Macpherson, Iain S; Striepen, Boris; Hedstrom, Lizbeth; Cuny, Gregory D

2012-01-24

137

Potential anticancer agents. XX. 2. Quantitative structure--activity relationships (QSAR) in aromatic nitrogen mustards area.  

PubMed

Quantitative structure--activity relationships have been fomulated for 27 aromatic nitrogen mustards derived from benzoic acids (9 monosubstituted and 18 disubstituted derivatives). Their toxicity (LD50) and antitumor activity against Jensen sarcoma were correlated with hydrolysis rate (log k66) lipophilicity constants (pi) and steric parameters (MDT). The chemical reactivity of the nitrogen mustard moiety (expressed as log k66) seems to be of main importance in determining the biological properties of these derivatives. The favorable effect of ortho-substitution was pointed out. Generally these results are in good agreement with those obtained by HANSCH et al. [7] on a different series of nitrogen mustards. PMID:7453847

Niculescu-Duv?z, I; Stihi, G; Cr?escu, T; Simon, Z

1980-01-01

138

Structure-activity relationships in non-ligand binding pocket (non-LBP) diarylhydrazide antiandrogens.  

PubMed

We report the synthesis and a study of the structure-activity relationships of a new series of diarylhydrazides as potential selective non-ligand binding pocket androgen receptor antagonists. Their biological activity as antiandrogens in the context of the development of treatments for castration resistant prostate cancer was evaluated using in vitro time resolved fluorescence resonance energy transfer and fluorescence polarization on target assays. Additionally, a theoretical study combining docking and molecular dynamics methods was performed to provide insight into their mechanism of action as a basis for further lead optimization studies. PMID:23834240

Caboni, Laura; Egan, Billy; Kelly, Brendan; Blanco, Fernando; Fayne, Darren; Meegan, Mary J; Lloyd, David G

2013-07-23

139

Structure-activity relationships of lanostane-type triterpenoids from Ganoderma lingzhi as ?-glucosidase inhibitors.  

PubMed

A series of lanostane-type triterpenoids, identified as ganoderma alcohols and ganoderma acids, were isolated from the fruiting body of Ganoderma lingzhi. Some of these compounds were confirmed as active inhibitors of the in vitro human recombinant aldose reductase. This paper aims to explain the structural requirement for ?-glucosidase inhibition. Our structure-activity studies of ganoderma alcohols showed that the OH substituent at C-3 and the double-bond moiety at C-24 and C-25 are necessary to increase ?-glucosidase inhibitory activity. The structure-activity relationships of ganoderma acids revealed that the OH substituent at C-11 is an important feature and that the carboxylic group in the side chain is essential for the recognition of ?-glucosidase inhibitory activity. Moreover, the double-bond moiety at C-20 and C-22 in the side chain and the OH substituent at C-3 of ganoderma acids improve ?-glucosidase inhibitory activity. These results provide an approach with which to consider the structural requirements of lanostane-type triterpenoids from G. lingzhi. An understanding of these requirements is considered necessary in order to improve a new type of ?-glucosidase inhibitor. PMID:24070782

Fatmawati, Sri; Kondo, Ryuichiro; Shimizu, Kuniyoshi

2013-09-05

140

Using a cloud electrification model to study relationships between lightning activity and cloud microphysical structure  

NASA Astrophysics Data System (ADS)

In this study a one-dimensional numerical cloud electrification model, called the Explicit Microphysics Thunderstorm Model (EMTM), is used to find quantitative relationships between the simulated electrical activity and microphysical properties in convective clouds. The model, based on an explicit microphysics scheme coupled to an ice-ice noninductive electrification scheme, allows us to interpret the connection of cloud microphysical structure with charge density distribution within the cloud, and to study the full evolution of the lightning activity (intracloud and cloud-to-ground) in relation to different environmental conditions. Thus, we apply the model to a series of different case studies over continental Europe and the Mediterranean region. We first compare, for selected case studies, the simulated lightning activity with the data provided by the ground-based Lightning Detection Network (LINET) in order to verify the reliability of the model and its limitations, and to assess its ability to reproduce electrical activity consistent with the observations. Then, using all simulations, we find a correlation between some key microphysical properties and cloud electrification, and derive quantitative relationships relating simulated flash rates to minimum thresholds of graupel mass content and updrafts. Finally, we provide outlooks on the use of such relationships and comments on the future development of this study.

Formenton, M.; Panegrossi, G.; Casella, D.; Dietrich, S.; Mugnai, A.; Sanò, P.; Di Paola, F.; Betz, H.-D.; Price, C.; Yair, Y.

2013-04-01

141

Structure-activity relationship of fenamates as Slo2.1 channel activators.  

PubMed

Niflumic acid, 2-{[3-(trifluoromethyl)phenyl]amino}pyridine-3-carboxylic acid (NFA), a nonsteroidal anti-inflammatory drug that blocks cyclooxygenase (COX), was shown previously to activate [Na(+)](i)-regulated Slo2.1 channels. In this study, we report that other fenamates, including flufenamic acid, mefenamic acid, tolfenamic acid, meclofenamic acid, and a phenyl acetic acid derivative, diclofenac, also are low-potency (EC(50) = 80 ?M to 2.1 mM), partial agonists of human Slo2.1 channels heterologously expressed in Xenopus oocytes. Substituent analysis determined that N-phenylanthranilic acid was the minimal pharmacophore for fenamate activation of Slo2.1 channels. The effects of fenamates were biphasic, with an initial rapid activation phase followed by a slow phase of current inhibition. Ibuprofen, a structurally dissimilar COX inhibitor, did not activate Slo2.1. Preincubation of oocytes with ibuprofen did not significantly alter the effects of NFA, suggesting that neither channel activation nor inhibition is associated with COX activity. A point mutation (A278R) in the pore-lining S6 segment of Slo2.1 increased the sensitivity to activation and reduced the inhibition induced by NFA. Together, our results suggest that fenamates bind to two sites on Slo2.1 channels: an extracellular accessible site to activate and a cytoplasmic accessible site in the pore to inhibit currents. PMID:22851714

Garg, Priyanka; Sanguinetti, Michael C

2012-07-31

142

Quinolone molecular structure-activity relationships: what we have learned about improving antimicrobial activity.  

PubMed

Recently, understanding of how molecular modifications of the core quinolone structure affect(s) antimicrobial agent activity has progressed rapidly. Three positions (2, 3, and 4) cannot be changed without a significant loss of biological activity. Furthermore, it appears that a cyclopropyl group is optimal at position 1. Substituents at positions 5 and 8 affect planar configuration, and either a methyl or methoxy appear optimal at these sites. Hydrogen and amino groups have been investigated as useful substituents at position 6, replacing the fluorine of the fluoroquinolones. Interestingly, in vitro activity enhancement observed with alterations at positions 5 and 6 is not always accompanied by improved in vivo action. For all these modifications, the substituents at positions 7 and 8 are critical for potent antimicrobial activity. Optimizing overall molecular configuration enhances the number of intracellular targets for antimicrobial action (R-8) and impedes the efficiency of efflux proteins (R-7) that diminish intracellular penetration. PMID:11524717

Peterson, L R

2001-09-15

143

In vitro cytotoxic activity and structure activity relationships of iridoid glucosides derived from Veronica species.  

PubMed

This study was an investigation of the cytotoxic activity of iridoid glucosides, including aucubin, catalpol, 6-O-acetylcatalpol, veronicoside, catalposide, verproside, amphicoside, veratroylcatalposide, verminoside, aquaticosides B and C isolated from different Veronica species. The cytotoxic activity was determined against Hep-2 (human epidermoid carcinoma), RD (human rhabdomyosarcoma), L-20B (transgenic murine L-cells) cancer cell lines and Vero (African green monkey kidney cells) non-cancerous cell line using the MTT method. While verminoside, amphicoside and veronicoside were found to exhibit cytotoxic activity in the concentration range of 70-355?µM, acetylcatalpol, aquaticosides B and C, catalposide, veratroylcatalposide and verproside showed cytostatic activity. Apoptotic cell death was observed as the effect of verminoside in the histological analysis of the tested cell lines. In conclusion, iridoid glucosides are considered to show a biphasic effect on cancer cells that is both cytostatic and cytotoxic, depending on the chemical structure and the type of cancer cell. PMID:21678519

Saracoglu, Iclal; Harput, U Sebnem

2011-06-16

144

Synthesis of hydroxypyrone- and hydroxythiopyrone-based matrix metalloproteinase inhibitors: Developing a structure-activity relationship  

PubMed Central

The zinc(II)-dependent matrix metalloproteinases (MMPs) are associated with a variety of diseases. Development of inhibitors to modulate MMP activity has been an active area of investigation for therapeutic development. Hydroxypyrones and hydroxythiopyrones are alternative zinc-binding groups (ZBGs) that, when combined with peptidomimetic backbones, comprise a novel class of MMP inhibitors (MMPi). In this report, a series of hydroxypyrone- and hydroxythiopyrone-based MMPi with aryl backbones at the 2-, 5-, and 6-positions of the hydroxypyrone ring have been synthesized. Synthetic routes for developing inhibitors with substituents at two of these positions (so-called double-handed inhibitors) are also explored. The MMP inhibition profiles and structure–activity relationship of synthesized hydroxypyrones and hydroxythiopyrones have been analyzed. The results here show that the ZBG, the position of the backbone on the ZBG, and the nature of the linker between the ZBG and backbone are critical for MMPi activities.

Yan, Yi-Long; Miller, Melissa T.; Cao, Yuchen; Cohen, Seth M.

2010-01-01

145

Structure-activity relationships of 1'-acetoxychavicol acetate homologues as new nuclear export signal inhibitors.  

PubMed

Bioassay-guided separation use of the fission yeast expressing NES of Rev, a HIV-1 viral regulatory protein, resulted in isolation of 1'-acetoxychavicol acetate (ACA) from Alpinia galanga as a new Rev-transport inhibitor from the nucleus to cytoplasm. Rational design and synthesis of eleven ACA derivatives containing systematic chemical variations were made, biological evaluation of inhibitory activities of these analogues provides the basis to formulate the structure-activity relationship (SAR). The key elements observed were: (1) The para substitution of the acetoxyl and 1'-acetoxypropenyl groups at the benzene ring was essential, (2) linear ethyl and propyl chain carbonates were more active than branching chain carbonates, (3) the substitution of acetoxyl groups with alkyl carbamate groups lost or reduced the activities. This study revealed a new salient pharmacophore features as potential drug leads against the HIV virus. PMID:17944317

Liu, Y; Murakami, N; Zhang, S; Xu, T

2007-09-01

146

Modular Synthesis of Heparan Sulfate Oligosaccharides for Structure-Activity Relationship Studies  

PubMed Central

Although hundreds of heparan sulfate binding proteins have been identified, and implicated in a myriad of physiological and pathological processes, very little information is known about ligand requirements for binding and mediating biological activities by these proteins. This difficulty results from a lack of technology for establishing structure-activity-relationships, which in turn is due to the structural complexity of natural heparan sulfate (HS) and difficulties of preparing well-defined HS-oligosaccharides. To address this deficiency, we have developed a modular approach for the parallel combinatorial synthesis of HS oligosaccharides that utilizes a relatively small number of selectively protected disaccharide building blocks, which can easily be converted into glycosyl donors and acceptors. The utility of the modular building blocks has been demonstrated by the preparation of a library of twelve oligosaccharides, which has been employed to probe structural features of HS for inhibiting the protease, BACE-1. The complex variations in activity with structural changes support the view that important functional information is embedded in HS sequences. Furthermore, the most active derivative provides an attractive lead compound for the preparation of more potent compounds, which may find use as a therapeutic agent for Alzheimer's disease.

Arungundram, Sailaja; Al-Mafraji, Kanar; Asong, Jinkeng; Leach, Franklin E.; Amster, I. Jonathan; Venot, Andre; Turnbull, Jeremy E.; Boons, Geert-Jan

2010-01-01

147

Novel orally active NPY Y5 receptor antagonists: Synthesis and structure-activity relationship of spiroindoline class compounds.  

PubMed

Spiroindoline urea derivatives, designed to act as NPY Y5 receptor antagonists, were synthesized and their structure-activity relationships were investigated. Of these derivatives, compound 3a showed good Y5 binding affinity with favorable pharmacokinetic properties. Compound 3a significantly inhibited bPP Y5 agonist-induced food intake in rats, and suppressed body weight gain in DIO mice. PMID:19525116

Sakamoto, Toshihiro; Moriya, Minoru; Tsuge, Hiroyasu; Takahashi, Toshiyuki; Haga, Yuji; Nonoshita, Katsumasa; Okamoto, Osamu; Takahashi, Hirobumi; Sakuraba, Aya; Hirohashi, Tomoko; Shibata, Takunobu; Kanno, Tetsuya; Ito, Junko; Iwaasa, Hisashi; Gomori, Akira; Ishihara, Akane; Fukuroda, Takahiro; Kanatani, Akio; Fukami, Takehiro

2009-06-02

148

A Receptor-Grounded Approach to Teaching Nonsteroidal Antiinflammatory Drug Chemistry and Structure-Activity Relationships  

PubMed Central

Objective To describe a receptor-based approach to promote learning about nonsteroidal anti-inflammatory drug (NSAID) chemistry, structure-activity relationships, and therapeutic decision-making. Design Three lessons on cyclooxygenase (COX) and NSAID chemistry, and NSAID therapeutic utility, were developed using text-based resources and primary medicinal chemistry and pharmacy practice literature. Learning tools were developed to assist students in content mastery. Assessment Student learning was evaluated via performance on quizzes and examinations that measured understanding of COX and NSAID chemistry, and the application of that knowledge to therapeutic problem solving. Conclusion Student performance on NSAID-focused quizzes and examinations documented the success of this approach.

2009-01-01

149

Applying quantitative structure-activity relationship approaches to nanotoxicology: Current status and future potential.  

PubMed

The potential (eco)toxicological hazard posed by engineered nanoparticles is a major scientific and societal concern since several industrial sectors (e.g. electronics, biomedicine, and cosmetics) are exploiting the innovative properties of nanostructures resulting in their large-scale production. Many consumer products contain nanomaterials and, given their complex life-cycle, it is essential to anticipate their (eco)toxicological properties in a fast and inexpensive way in order to mitigate adverse effects on human health and the environment. In this context, the application of the structure-toxicity paradigm to nanomaterials represents a promising approach. Indeed, according to this paradigm, it is possible to predict toxicological effects induced by chemicals on the basis of their structural similarity with chemicals for which toxicological endpoints have been previously measured. These structure-toxicity relationships can be quantitative or qualitative in nature and they can predict toxicological effects directly from the physicochemical properties of the entities (e.g. nanoparticles) of interest. Therefore, this approach can aid in prioritizing resources in toxicological investigations while reducing the ethical and monetary costs that are related to animal testing. The purpose of this review is to provide a summary of recent key advances in the field of QSAR modelling of nanomaterial toxicity, to identify the major gaps in research required to accelerate the use of quantitative structure-activity relationship (QSAR) methods, and to provide a roadmap for future research needed to achieve QSAR models useful for regulatory purposes. PMID:23165187

Winkler, David A; Mombelli, Enrico; Pietroiusti, Antonio; Tran, Lang; Worth, Andrew; Fadeel, Bengt; McCall, Maxine J

2012-11-16

150

Structure-activity relationship of (-) mammea A/BB derivatives against Leishmania amazonensis.  

PubMed

To study the structure-activity relationship of coumarin (-) mammea A/BB isolated from the CH(2)Cl(2) extract of Calophyllum brasiliense leaves, we evaluated the antileishmanial activity of natural, synthetic and derivatives of this coumarin, against promastigote and intracellular amastigote forms of Leishmania amazonensis, and their cytotoxicity to J774G8 murine macrophages. The derivatives were obtained by hydrogenation and methoxylation reactions. The compound structures were elucidated on the basis of spectroscopic data. The compounds 5,7-dihydroxy-8-(2-methylbutanoyl)-6-(3-methylbutyl)-4-phenyl-chroman-2-one (3), 7-hydroxy-5-methoxy-8-(2-methylbutanoyl)-6-(3-methylbut-2-en-1-yl)-4-phenylcoumarin (4) and 5,7-dimethoxy-8-(1-methoxy-2-methylbutyl)-6-(3-methylbut-2-en-1-yl)-4 phenylcoumarin (6) were more biologically active than the compound (-) mammea A/BB (1) (7.4 microM), with IC(50) values from 0.9, 2.4 and 1.9 microM respectively; compound (3) displayed the highest activity. The compounds mammea B/BB (2), 5,7-dimethoxy-8-(2-methylbutanoyl)-6-(3-methylbut-2-en-1-yl)-4-phenylcoumarin (5) and 5,7-dihydroxy-4-phenylcoumarin (7) were less active than (-) mammea A/BB (1), with IC(50) of 30.1, 15.1 and 60.2 microM respectively; compound (7) showed the lowest antileishmanial activity of all. Compounds (1), (3), (4) and (6) were active not only against promastigote forms of L. amazonensis, but also against intracellular amastigote forms with IC(50) of 14.3, 0.6, 34.0 and 22.2 microM, respectively. Interestingly, compound (3) showed the most antileishmanial activity of all. This study demonstrated that several aspects of the structure were important for antileishmanial activity. PMID:18849135

Brenzan, Mislaine Adriana; Nakamura, Celso Vataru; Dias Filho, Benedito Prado; Ueda-Nakamura, Tânia; Young, Maria Claudia M; Côrrea, Arlene Gonçalves; Alvim, Joel; dos Santos, Adriana Oliveira; Cortez, Diógenes Aparício Garcia

2008-09-17

151

Neurotensin and neurotensin receptors: Characteristic, structure-activity relationship and pain modulation-A review.  

PubMed

Neurotensin (NT) is a tridecapeptide, which - since its discovery in 1973 - has been demonstrated to be involved in the control of various physiological activities in both the central nervous system and in the periphery. Its biological effects are mediated by four receptor types. Exogenously administered NT exerts different behavioral effects, including antinociception. Structure-activity relationship studies performed in recent years resulted in development of several peptidomimetic receptor agonists and non-peptidic receptor antagonists that are useful tools for studies of NT mechanisms in tissue and on cellular level. This may result in design of new generation of analgesics based on neurotensin. NT antinociceptive effects are distinct from opioid analgesia. This creates opportunity of development of hybride analgesics that may simultaneously activate both opioid and NT antinociceptive pathways. PMID:23500196

Kleczkowska, Patrycja; Lipkowski, Andrzej W

2013-03-14

152

Structure-activity relationship studies of novel glycosphingolipids that stimulate natural killer T-cells.  

PubMed

KRN7000, an anticancer drug candidate developed by Kirin Brewery Co. in 1995, is an ?-galactosyl ceramide. It is a ligand making a complex with CD1d protein, and it stimulates invariant natural killer T (NKT) cells, which are one of the lineages of immunocytes. NKT cells activated by recognition of the CD1d/KRN7000 complex with its invariant T-cell receptor (TCR) can induce both protective and regulatory immune responses. To determine the recognition and activation mechanisms of NKT cells and to develop drug candidates more effective than KRN7000, a large number of analogs of KRN7000 have been synthesized. Some of them show potent bioactivities and have the potential of being utilized as therapeutic agents. In this review, structure-activity relationship studies of novel glycolipids which stimulate NKT cells efficiently are summarized. PMID:22790924

Tashiro, Takuya

2012-06-07

153

Lead finding for acetyl cholinesterase inhibitors from natural origin: structure activity relationship and scope.  

PubMed

Acetylcholinesterase (AChE) inhibitors are considered as promising therapeutic agents for the treatment of several neurological disorders such as Alzheimer's disease (AD), senile dementia, ataxia and myasthenia gravis. There are only few synthetic medicines with adverse effects, available for treatment of cognitive dysfunction and memory loss associated with these diseases. A variety of plants has been reported to possess AChE inhibitory activity and so may be relevant to the treatment of neurodegenerative disorders such as AD. Hence, developing potential AChE inhibitors from botanicals is the need of the day. This review will cover some of the promising acetylcholinesterase inhibitors isolated from plants with proven in vitro and in vivo activities with concern to their structure activity relationship. PMID:21222577

Mukherjee, P K; Satheeshkumar, N; Venkatesh, P; Venkatesh, M

2011-03-01

154

A structure-activity relationship for induction of meningeal inflammation by muramyl peptides.  

PubMed Central

Components of bacterial peptidoglycans have potent biological activities, including adjuvant effects, cytotoxicity, and induction of sleep. Mixtures of peptidoglycan components also induce inflammation in the lung, subarachnoid space, and joint, but the structural requirements for activity are unknown. Using a rabbit model for meningitis, we determined the biological activities of 14 individual muramyl peptides constituting > 90% of the peptidoglycan of the gram-negative pediatric pathogen Haemophilus influenzae. Upon intracisternal inoculation, most of the muropeptides induced leukocytosis in cerebrospinal fluid (CSF), influx of protein into CSF, or brain edema, alone or in combination. The disaccharide-tetrapeptide, the major component of all gram-negative peptidoglycans, induced CSF leukocytosis and protein influx at doses as low as 0.4 microgram (0.42 nM). Modification of the N-acetyl muramic acid or substitution of the alanine at position four in the peptide side chain decreased leukocytosis but enhanced brain edema. As the size of the muropeptide increased, the inflammatory activity decreased. Muropeptide carrying the diaminopimelyl-diaminopimelic acid cross-link specifically induced cytotoxic brain edema. These findings significantly expand the spectrum of biological activities of natural muramyl peptides and provide the basis for a structure-activity relationship for the inflammatory properties of bacterial muropeptides.

Burroughs, M; Rozdzinski, E; Geelen, S; Tuomanen, E

1993-01-01

155

Structure-activity relationships of novel substituted naphthalene diimides as anticancer agents.  

PubMed

Novel 1,4,5,8-naphthalenetetracarboxylic diimide (NDI) derivatives were synthesized and evaluated for their antiproliferative activity on a wide number of different tumor cell lines. The prototypes of the present series were derivatives 1 and 2 characterized by interesting biological profiles as anticancer agents. The present investigation expands on the study of structure-activity relationships of prototypes 1 and 2, namely, the influence of the different substituents of the phenyl rings on the biological activity. Derivatives 3-22, characterized by a different substituent on the aromatic rings and/or a different chain length varying from two to three carbon units, were synthesized and evaluated for their cytostatic and cytotoxic activities. The most interesting compound was 20, characterized by a linker of three methylene units and a 2,3,4-trimethoxy substituent on the two aromatic rings. It displayed antiproliferative activity in the submicromolar range, especially against some different cell lines, the ability to inhibit Taq polymerase and telomerase, to trigger caspase activation by a possible oxidative mechanism, to downregulate ERK 2 protein and to inhibit ERKs phosphorylation, without acting directly on microtubules and tubuline. Its theoretical recognition against duplex and quadruplex DNA structures have been compared to experimental thermodynamic measurements and by molecular modeling investigation leading to putative binding modes. Taken together these findings contribute to define this compound as potential Multitarget-Directed Ligands interacting simultaneously with different biological targets. PMID:22819507

Milelli, Andrea; Tumiatti, Vincenzo; Micco, Marialuisa; Rosini, Michela; Zuccari, Guendalina; Raffaghello, Lizzia; Bianchi, Giovanna; Pistoia, Vito; Fernando Díaz, J; Pera, Benet; Trigili, Chiara; Barasoain, Isabel; Musetti, Caterina; Toniolo, Marianna; Sissi, Claudia; Alcaro, Stefano; Moraca, Federica; Zini, Maddalena; Stefanelli, Claudio; Minarini, Anna

2012-07-04

156

A review on structure-activity relationship of dietary polyphenols inhibiting ?-amylase.  

PubMed

The inhibitory effects of dietary polyphenols against ?-amylase have attracted great interest among researchers. The aim of this review is to give an overview of the research reports on the structure-activity relationship of polyphenols inhibiting ?-amylase. The molecular structures that influence the inhibition are the following: (1) The hydroxylation of flavonoids improved the inhibitory effect on ?-amylase; (2) Presence of an unsaturated 2,3-bond in conjugation with a 4-carbonyl group has been associated with stronger inhibition; (3) The glycosylation of flavonoids decreased the inhibitory effect on ?-amylase depending on the conjugation site and the class of sugar moiety; (4) The methylation and methoxylation of flavonoids obviously weakened the inhibitory effect; (5) The galloylated catechins have higher inhibition than nongalloylated catechins; the catechol-type catechins were stronger than the pyrogallol-type catechins; the inhibition activities of the catechins with 2,3-trans structure were higher than those of the catechins with 2,3-cis structure; (6) Cyanidin-3-glucoside showed higher inhibition against than cyanidin and cyanidin-3-galactoside and cyanidin-3,5-diglucoside had no inhibitory activity; (7) Ellagitannins with ?-galloyl groups at glucose C-1 positions have higher inhibitory effect than the ?-galloyl and nongalloyl compounds and the molecular weight of ellagitannins is not an important element. PMID:23391016

Xiao, Jianbo; Ni, Xiaoling; Kai, Guoyin; Chen, Xiaoqing

2013-01-01

157

Fundamental Structure-Activity Relationships of Titanium Dioxide-Based Photocatalysts  

NASA Astrophysics Data System (ADS)

Heterogeneous photocatalysis has been identified as a means of using renewable solar energy to produce the sustainable, non-carbon fuel H 2 and a variety of useful chemical intermediates. Currently, however, heterogeneous photocatalytic reactions are too inefficient to be industrially relevant and a deeper understanding of the effect of fundamental photocatalytic material properties on photoactivity is needed to further enhance the yields of desired products. In the general field of heterogeneous catalysis, structure-activity relationships aid in the rational design of improved catalysts and this ideology was applied to photocatalytic reactions over TiO2 based photocatalysts and model supported TiO2/SiO2 catalysts in this study. The model supported TiO2/SiO2 catalysts contain well-defined TiOx nanodomain structures that vary in domain size and electronic structure and greatly facilitate the determination of structure-photoactivity relationships. These catalysts were used in reactor studies during photocatalytic water splitting and cyclohexane photo-oxidation, and were monitored for production of H2 and cyclohexanone, respectively. It was found that for both reactions the trend in photoactivity for the TiOx nanodomains proceeded as: pure TiO2 (anatase) (24 nm) > TiO2 (anatase) nanoparticles (4--11 nm) > polymeric surface TiO5 (˜1 nm) > surface isolated TiO4 (˜0.4 nm). Photoluminescence (PL) spectroscopy was employed to yield insight into how exciton generation and recombination are related to TiOx domain size and, thus, to the photoactivity of the examined reactions. Transient PL decay studies determined that the larger bulk structure found in TiO 2 (anatase) nanoparticles (NPs) acts as a reservoir for excitons exhibiting slow recombination kinetics, which have an increased opportunity to participate in photochemistry at the surface active sites. The reactions were also studied using in situ attenuated total reflectance (ATR) Fourier transform infrared spectroscopy (FTIR) to observe the formation of adsorbed intermediates and products. For cyclohexane photo-oxidation, cyclohexanone intermediates and products were identified and the high photoactivity of the unsupported TiO2 (anatase) NPs was attributed to improved product desorption characteristics. The identification of intermediates during water splitting is made difficult by the extremely high absorption of infrared wavelengths by H2O. ATR-FTIR and Raman spectroscopy measurements were performed during photocatalytic splitting of water in an attempt to confirm the surface reaction intermediates currently identified in the literature and evidence for both superoxide (O2-) and peroxide (O2 2-) adsorbed species were found by ATR-FTIR, but no surface Ti-OOH was detected by Raman. Finally, alternate Ti-containing structures, titanate and TiO2 (anatase) nanotubes, were characterized with Raman spectroscopy and screened for their photocatalytic activity. Depending on the photo-reaction (4-chlorophenol decomposition or water splitting), thermal treatment to form the anatase phase in the nanotubular structure is a benefit to photoactivity due to the increased crystallinity. For water splitting, however, the structure-activity relationship found for supported TiO 2/SiO2 holds, and the presence of a larger bulk structure yields the best H2 production photoactivity. The structure-photoactivity relationship in this dissertation exists for two different photo-reactions and is expected to be a beneficial aid to future studies on the rational design of new and novel photocatalysts.

Roberts, Charles A.

158

Localized heuristic inverse quantitative structure activity relationship with bulk descriptors using numerical gradients.  

PubMed

State-of-the-art quantitative structure-activity relationship (QSAR) models are often based on nonlinear machine learning algorithms, which are difficult to interpret. From a pharmaceutical perspective, QSARs are used to enhance the chemical design process. Ultimately, they should not only provide a prediction but also contribute to a mechanistic understanding and guide modifications to the chemical structure, promoting compounds with desirable biological activity profiles. Global ranking of descriptor importance and inverse QSAR have been used for these purposes. This paper introduces localized heuristic inverse QSAR, which provides an assessment of the relative ability of the descriptors to influence the biological response in an area localized around the predicted compound. The method is based on numerical gradients with parameters optimized using data sets sampled from analytical functions. The heuristic character of the method reduces the computational requirements and makes it applicable not only to fragment based methods but also to QSARs based on bulk descriptors. The application of the method is illustrated on congeneric QSAR data sets, and it is shown that the predicted influential descriptors can be used to guide structural modifications that affect the biological response in the desired direction. The method is implemented into the AZOrange Open Source QSAR package. The current implementation of localized heuristic inverse QSAR is a step toward a generally applicable method for elucidating the structure activity relationship specifically for a congeneric region of chemical space when using QSARs based on bulk properties. Consequently, this method could contribute to accelerating the chemical design process in pharmaceutical projects, as well as provide information that could enhance the mechanistic understanding for individual scaffolds. PMID:23845139

Stålring, Jonna; Almeida, Pedro R; Carlsson, Lars; Helgee Ahlberg, Ernst; Hasselgren, Catrin; Boyer, Scott

2013-07-25

159

Structure-activity relationships in toll-like receptor 2-agonists leading to simplified monoacyl lipopeptides.  

PubMed

Toll-like receptor 2-agonistic lipopeptides typified by S-[2,3-bis(palmitoyloxy)-(2RS)-propyl]-R-cysteinyl-S-serine (PAM(2)CS) compounds are potential vaccine adjuvants. In continuation of previously reported structure-activity relationships on this chemotype, we have determined that at least one acyl group of optimal length (C(16)) and an appropriately oriented ester carbonyl group is essential for TLR2-agonistic activity. The spacing between one of the palmitoyl ester carbonyl and the thioether is crucial to allow for an important H-bond, which observed in the crystal structure of the lipopeptide:TLR2 complex; consequently, activity is lost in homologated compounds. Penicillamine-derived analogues are also inactive, likely due to unfavorable steric interactions with the carbonyl of Ser 12 in TLR2. The thioether in this chemotype can be replaced with a selenoether. Importantly, the thioglycerol motif can be dispensed with altogether and can be replaced with a thioethanol bridge. These results have led to a structurally simpler, synthetically more accessible, and water-soluble analogue possessing strong TLR2-agonistic activities in human blood. PMID:22007676

Agnihotri, Geetanjali; Crall, Breanna M; Lewis, Tyler C; Day, Timothy P; Balakrishna, Rajalakshmi; Warshakoon, Hemamali J; Malladi, Subbalakshmi S; David, Sunil A

2011-11-04

160

Structure-Activity Relationships in Toll-like Receptor 2-Agonists Leading to Simplified Monoacyl Lipopeptides  

PubMed Central

Toll-like receptor 2-agonistic lipopeptides typified by S-[2,3-bis(palmitoyloxy)-(2RS)-propyl]-R-cysteinyl-S-serine (PAM2CS) compounds are potential vaccine adjuvants. In continuation of previously reported structure-activity relationships on this chemotype, we have determined that at least one acyl group of optimal length (C16) and an appropriately orientated ester carbonyl group is essential for TLR2-agonistic activity. The spacing between one of the palmitoyl ester carbonyl and the thioether is crucial to allow for an important H-bond, which observed in the crystal structure of the lipopeptide:TLR2 complex; consequently, activity is lost in homologated compounds. Penicillamine-derived analogues are also inactive, likely due to unfavorable steric interactions with the carbonyl of Ser 12 in TLR2. The thioether in this chemotype can be replaced with a selenoether. Importantly, the thioglycerol motif can be dispensed with altogether, and can be replaced with a thioethanol bridge. These results have led to a structurally simpler, synthetically more accessible, and water-soluble analogue possessing strong TLR2-agonistic activities in human blood.

Agnihotri, Geetanjali; Crall, Breanna M.; Lewis, Tyler C.; Day, Timothy P.; Balakrishna, Rajalakshmi; Warshakoon, Hemamali J.; Malladi, Subbalakshmi S.; David, Sunil A.

2011-01-01

161

ESTIMATION OF MICROBIAL REDUCTIVE TRANSFORMATION RATES FOR CHLORINATED BENZENES AND PHENOLS USING A QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIP APPROACH  

EPA Science Inventory

A set of literature data was used to derive several quantitative structure-activity relationships (QSARs) to predict the rate constants for the microbial reductive dehalogenation of chlorinated aromatics. Dechlorination rate constants for 25 chloroaromatics were corrected for th...

162

FISH ACUTE TOXICITY SYNDROMES: APPLICATION TO THE DEVELOPMENT OF MECHANISM-SPECIFIC QSARS (QUANTITATIVE STRUCTURE ACTIVITY RELATIONSHIPS)  

EPA Science Inventory

Predictive models based on quantitative structure activity relationships (QSARs), are used as rapid screening tools to identify potentially hazardous chemicals. Several QSARs are now available that predict the acute toxicity of narcotic-industrial chemicals. Predictions for compo...

163

Structure-Activity Relationship Studies on the Macrolide Exotoxin Mycolactone of Mycobacterium ulcerans  

PubMed Central

Background Mycolactones are a family of polyketide-derived macrolide exotoxins produced by Mycobacterium ulcerans, the causative agent of the chronic necrotizing skin disease Buruli ulcer. The toxin is synthesized by polyketide synthases encoded by the virulence plasmid pMUM. The apoptotic, necrotic and immunosuppressive properties of mycolactones play a central role in the pathogenesis of M. ulcerans. Methodology/Principal Findings We have synthesized and tested a series of mycolactone derivatives to conduct structure-activity relationship studies. Flow cytometry, fluorescence microscopy and Alamar Blue-based metabolic assays were used to assess activities of mycolactones on the murine L929 fibroblast cell line. Modifications of the C-linked upper side chain (comprising C12–C20) caused less pronounced changes in cytotoxicity than modifications in the lower C5-O-linked polyunsaturated acyl side chain. A derivative with a truncated lower side chain was unique in having strong inhibitory effects on fibroblast metabolism and cell proliferation at non-cytotoxic concentrations. We also tested whether mycolactones have antimicrobial activity and found no activity against representatives of Gram-positive (Streptococcus pneumoniae) or Gram-negative bacteria (Neisseria meningitis and Escherichia coli), the fungus Saccharomyces cerevisae or the amoeba Dictyostelium discoideum. Conclusion Highly defined synthetic compounds allowed to unambiguously compare biological activities of mycolactones expressed by different M. ulcerans lineages and may help identifying target structures and triggering pathways.

Scherr, Nicole; Gersbach, Philipp; Dangy, Jean-Pierre; Bomio, Claudio; Li, Jun; Altmann, Karl-Heinz; Pluschke, Gerd

2013-01-01

164

Structure-activity relationships in toll-like receptor-2 agonistic diacylthioglycerol lipopeptides.  

PubMed

The N-termini of bacterial lipoproteins are acylated with a (S)-(2,3-bisacyloxypropyl)cysteinyl residue. Lipopeptides derived from lipoproteins activate innate immune responses by engaging Toll-like receptor 2 (TLR2) and are highly immunostimulatory and yet without apparent toxicity in animal models. The lipopeptides may therefore be useful as potential immunotherapeutic agents. Previous structure-activity relationships in such lipopeptides have largely been obtained using murine cells, and it is now clear that significant species-specific differences exist between human and murine TLR responses. We have examined in detail the role of the highly conserved Cys residue as well as the geometry and stereochemistry of the Cys-Ser dipeptide unit. (R)-Diacylthioglycerol analogues are maximally active in reporter gene assays using human TLR2. The Cys-Ser dipeptide unit represents the minimal part-structure, but its stereochemistry was found not to be a critical determinant of activity. The thioether bridge between the diacyl and dipeptide units is crucial, and replacement by an oxoether bridge results in a dramatic decrease in activity. PMID:20302301

Wu, Wenyan; Li, Rongti; Malladi, Subbalakshmi S; Warshakoon, Hemamali J; Kimbrell, Matthew R; Amolins, Michael W; Ukani, Rehman; Datta, Apurba; David, Sunil A

2010-04-22

165

Structure-activity relationship analysis of the selective inhibition of transglutaminase 2 by dihydroisoxazoles.  

PubMed

Human transglutaminase 2 (TG2) is believed to play an important role in the pathogenesis of various human disorders including celiac sprue, certain neurological diseases, and some types of cancer. Selective inhibition of TG2 should therefore enable further investigation of its role in physiology and disease and may lead to effective clinical treatment. Recently we showed that certain 3-halo-4-,5-dihydroisoxazole containing compounds are selective inhibitors of human TG2 with promising pharmacological activities. Here, we present definitive evidence that this class of compounds targets the active site of human TG2. Structure-activity relationship studies have provided insights into the structural prerequisites for selectivity and have led to the discovery of an inhibitor with about 50-fold higher activity than a prototypical dihydroisoxazole inhibitor with good in vivo activity. A method for preparing enantiomerically enriched analogues was also developed. Our studies show that the 5-(S)-dihydroisoxazole is a markedly better inhibitor of human TG2 than its 5-(R) stereoisomer. PMID:17149878

Watts, R Edward; Siegel, Mathew; Khosla, Chaitan

2006-12-14

166

Structure-Activity Relationships in Toll-like Receptor-2 agonistic Diacylthioglycerol Lipopeptides  

PubMed Central

The N-termini of bacterial lipoproteins are acylated with a (S)-(2,3-bisacyloxypropyl)cysteinyl residue. Lipopeptides derived from lipoproteins activate innate immune responses by engaging Toll-like receptor 2 (TLR2), and are highly immunostimulatory and yet without apparent toxicity in animal models. The lipopeptides may therefore be useful as potential immunotherapeutic agents. Previous structure-activity relationships in such lipopeptides have largely been obtained using murine cells and it is now clear that significant species-specific differences exist between human and murine TLR responses. We have examined in detail the role of the highly conserved Cys residue as well as the geometry and stereochemistry of the Cys-Ser dipeptide unit. (R)-diacylthioglycerol analogues are maximally active in reporter gene assays using human TLR2. The Cys-Ser dipeptide unit represents the minimal part-structure, but its stereochemistry was found not to be a critical determinant of activity. The thioether bridge between the diacyl and dipeptide units is crucial, and replacement by an oxoether bridge results in a dramatic decrease in activity.

Wu, Wenyan; Li, Rongti; Malladi, Subbalakshmi S.; Warshakoon, Hemamali J.; Kimbrell, Matthew R.; Amolins, Michael W.; Ukani, Rehman; Datta, Apurba; David, Sunil A.

2010-01-01

167

Chemical Sensor Array Response Modeling Using Quantitative Structure-Activity Relationships Technique  

NASA Astrophysics Data System (ADS)

We have developed a Quantitative Structure-Activity Relationships (QSAR) based approach to correlate the response of chemical sensors in an array with molecular descriptors. A novel molecular descriptor set has been developed; this set combines descriptors of sensing film-analyte interactions, representing sensor response, with a basic analyte descriptor set commonly used in QSAR studies. The descriptors are obtained using a combination of molecular modeling tools and empirical and semi-empirical Quantitative Structure-Property Relationships (QSPR) methods. The sensors under investigation are polymer-carbon sensing films which have been exposed to analyte vapors at parts-per-million (ppm) concentrations; response is measured as change in film resistance. Statistically validated QSAR models have been developed using Genetic Function Approximations (GFA) for a sensor array for a given training data set. The applicability of the sensor response models has been tested by using it to predict the sensor activities for test analytes not considered in the training set for the model development. The validated QSAR sensor response models show good predictive ability. The QSAR approach is a promising computational tool for sensing materials evaluation and selection. It can also be used to predict response of an existing sensing film to new target analytes.

Shevade, Abhijit V.; Ryan, Margaret A.; Homer, Margie L.; Zhou, Hanying; Manfreda, Allison M.; Lara, Liana M.; Yen, Shiao-Pin S.; Jewell, April D.; Manatt, Kenneth S.; Kisor, Adam K.

168

Discovery and structure-activity relationships of 6-(benzoylamino)benzoxaboroles as orally active anti-inflammatory agents.  

PubMed

Structure-activity relationships of 6-(benzoylamino)benzoxaborole analogs were investigated for the inhibition of TNF-?, IL-1?, and IL-6 from lipopolysaccharide stimulated peripheral blood mononuclear cells. Compound 1q showed potent activity against all three cytokines with IC50 values between 0.19 and 0.50?M, inhibited LPS-induced TNF-? and IL-6 elevation in mice and improved collagen-induced arthritis in mice. Compound 1q (AN4161) is considered to be a promising lead for novel anti-inflammatory agent with an excellent pharmacokinetic profile. PMID:24075731

Akama, Tsutomu; Dong, Chen; Virtucio, Charlotte; Freund, Yvonne R; Chen, Daitao; Orr, Matthew D; Jacobs, Robert T; Zhang, Yong-Kang; Hernandez, Vincent; Liu, Yang; Wu, Anne; Bu, Wei; Liu, Liang; Jarnagin, Kurt; Plattner, Jacob J

2013-09-06

169

Adsorption kinetics of alkanes on TiO2 nanotubesarray structure activity relationship  

NASA Astrophysics Data System (ADS)

Presented are thermal desorption spectroscopy (TDS) measurements of iso-/n-butane adsorption on a variety of TiO2 nanotubes (TiNTs) samples which are characterized by different crystal structures. The results are compared with a prior study on anatase(0 0 1) thin films grown on SrTiO3(0 0 1). A distinct kinetic structure activity relationship was present, i.e., the binding energies of the alkanes depend on the polymorph (anatase vs. mixed anatase/rutile) of TiO2. A direct-fitting procedure of the TDS data has been applied to extract the kinetics parameters. The binding energies in the limit of zero coverage decrease as anatase thin film > amorphous-TiNTs ˜ polycrystalline anatase TiNTs > polycrystalline mixed anatase/rutile TiNTs.

Hokkanen, B.; Funk, S.; Burghaus, U.; Ghicov, A.; Schmuki, P.

2007-10-01

170

Structure activity relationships of cycloalkylamide derivatives as inhibitors of the soluble epoxide hydrolase  

PubMed Central

Structure activity relationships of cycloalkylamide compounds as inhibitors of human sEH were investigated. When the left side of amide function was modified by a variety of cycloalkanes, at least a C6 like cyclohexane was necessary to yield reasonable inhibition potency on the target enzyme. In compounds with a smaller cycloalkane or with a polar group on the left side of amide function, no inhibition was observed. On the other hand, increased hydrophobicity dramatically improved inhibition potency. Especially, a tetrahydronaphthalene (20) effectively increased the potency. When a series of alkyl or aryl derivatives of cycloalkylamide were investigated to continuously optimize the right side of the amide pharmacophore, a benzyl moiety functionalized with a polar group produced highly potent inhibition. Non-substituted benzyl, alkyl, aryl, or biaryl structure present in the right side of cycloalkylamide function induced a big decrease in inhibition potency. Also, a resulting potent cycloalkylamide (32) showed reasonable physical properties.

Kim, In-Hae; Park, Yong-Gyu; Hammock, Bruce D.; Nishi, Kosuke

2012-01-01

171

Bioisosterism of urea-based GCPII inhibitors: Synthesis and structure?activity relationship studies  

SciTech Connect

We report a strategy based on bioisosterism to improve the physicochemical properties of existing hydrophilic, urea-based GCPII inhibitors. Comprehensive structure-activity relationship studies of the P1{prime} site of ZJ-43- and DCIBzL-based compounds identified several glutamate-free inhibitors with K{sub i} values below 20 nM. Among them, compound 32d (K{sub i} = 11 nM) exhibited selective uptake in GCPII-expressing tumors by SPECT-CT imaging in mice. A novel conformational change of amino acids in the S1{prime} pharmacophore pocket was observed in the X-ray crystal structure of GCPII complexed with 32d.

Wang, Haofan; Byun, Youngjoo; Barinka, Cyril; Pullambhatla, Mrudula; Bhang, Hyo-eun C.; Fox, James J.; Lubkowski, Jacek; Mease, Ronnie C.; Pomper, Martin G. (NCI); (JHMI)

2010-10-28

172

Relationships between structure and activity of carbon as a multifunctional support for electrocatalysts.  

PubMed

We report on new insights into the relationships between structure and activity of glassy carbon (GC), as a model material for electrocatalyst support, during its anodization in acid solution. Our investigation strongly confirms the role of CFGs in promotion of Pt activity by the "spill-over" effect related to CO(ads) for methanol electrooxidation (MEO) on a carbon-supported Pt catalyst. Combined analysis of voltammetric and impedance behaviour as well as changes in GC surface morphology induced by intensification of anodizing conditions reveal an intrinsic influence of the carbon functionalization and the structure of a graphene oxide (GO) layer on the electrical and electrocatalytic properties of activated GC. Although GO continuously grows during anodization, it structurally changes from being a graphite inter-layer within graphite ribbons toward a continuous GO surface layer that deteriorates the native structure of GC. As a consequence of the increased distance between GO-spaced graphite layers, the GC conductivity decreases until the case of profound GO exfoliation under drastic anodizing conditions. This exposes the native, yet abundantly functionalized, GC texture. While GC capacitance continuously increases with intensification of anodizing conditions, the surface nano-roughness and GO resistance reach the highest values at modest anodizing conditions, and then decrease upon drastic anodization due to the onset of GO exfoliation. We found for the first time that the activity of a GC-supported Pt catalyst in MEO, as one of the promising half-reactions in polymer electrolyte fuel cells, strictly follows the changes in GC nano-roughness and GO-induced GC resistance. The highest GC/Pt MEO activity is reached when optimal distance between graphite layers and optimal degree of GC functionalization bring the highest amount of CFGs into intimate contact with the Pt surface. This confirms the promoting role of CFGs in MEO catalysis. PMID:22648036

Stevanovi?, Sanja I; Pani?, Vladimir V; Dekanski, Aleksandar B; Tripkovi?, Amalija V; Jovanovi?, Vladislava M

2012-05-30

173

Quantitative structure-activity relationships of imidazolium oximes as nerve agent antidotes  

SciTech Connect

Organophosphorus-containing pesticides and chemical warfare agents are potent inhibitors of synaptic acetylcholinesterase, a key regulator of cholinergic neurotransmission. These nerve agents have for many years constituted a serious threat to military personnel. These threats stimulated considerable efforts to develop effective medical countermeasures. Several potential drugs have been found recently which are capable of protecting animals from lethal levels of nerve agents. A recent U. S. Army Medical Research and Development Command drug development project synthesized a large number of imidazolium oximes. These compounds were found to possess strong antidotal activity against one of the most lethal nerve agents, soman. The Army's approach, like most conventional drug discovery approaches, depended primarily on the trial and error method. This research was carried out to determine if these potential nerve agent antidotes could have been discovered through the use of Quantitative Structure Activity-Relationships (QSAR) technique.

Musallam, H.A.; Foye, W.O.; Hansch, C.; Harris, R.N.; Engle, R.R.

1993-05-13

174

Structure-activity relationships and in silico models of P-glycoprotein (ABCB1) inhibitors.  

PubMed

Abstract 1. The efflux pump p-glycoprotein (P-gp/ABCB1) has received enormous attention in drug (xenobiotic) disposition due to its role in modulation of the drug availability and in protection of sensitive organs. 2. P-gp mediated efflux is one of main mechanisms for multidrug resistance in cancer cells. A main approach to reverse the resistance and restore the drug efficacy is to use specific inhibitors of P-gp that suppress the efflux activity. 3. This review summarizes the binding capabilities of known chemical inhibitors based on the analyses of structure-activity relationships, and computational modeling of the inhibitors as well as the binding site of P-gp protein. 4. The molecular models will facilitate the design of lead inhibitors as drug candidates. Also, it helps scientists in early drug discovery phase to synthesize chemical series with better understanding of their P-gp binding liabilities. PMID:23617855

Liu, Hongming; Ma, Zhiguo; Wu, Baojian

2013-04-25

175

Tyrosinase inhibition studies of cycloartane and cucurbitane glycosides and their structure-activity relationships.  

PubMed

In the present paper, tyrosinase inhibition studies and structure-activity relationship of eight cycloartane glycosides and one cucurbitane glycoside and its genin, which were isolated from Astragalus (Leguminoseae) and Bryonia (Cucurbitaceae) plants, have been discussed. The activities are compared with two reference tyrosinase inhibitors, kojic acid and l-mimosine. These studies and the SAR showed that the askendoside B which exhibited highly potent (IC50 =13.95 microM) tyrosinase inhibition could be a possible lead molecule for the development of new medications of several skin diseases related with the over-expression of the enzyme tyrosinase, like hyperpigmentation. The molecule also may be interesting for the cosmetic industries as a skin whitening agent. PMID:16716596

Khan, Mahmud Tareq Hassan; Choudhary, M Iqbal; Atta-ur-Rahman; Mamedova, Reyhan P; Agzamova, Manzura A; Sultankhodzhaev, Mukhlis N; Isaev, Mahamed I

2006-05-23

176

Interpretable, probability-based confidence metric for continuous quantitative structure-activity relationship models.  

PubMed

A great deal of research has gone into the development of robust confidence in prediction and applicability domain (AD) measures for quantitative structure-activity relationship (QSAR) models in recent years. Much of the attention has historically focused on structural similarity, which can be defined in many forms and flavors. A concept that is frequently overlooked in the realm of the QSAR applicability domain is how the local activity landscape plays a role in how accurate a prediction is or is not. In this work, we describe an approach that pairs information about both the chemical similarity and activity landscape of a test compound's neighborhood into a single calculated confidence value. We also present an approach for converting this value into an interpretable confidence metric that has a simple and informative meaning across data sets. The approach will be introduced to the reader in the context of models built upon four diverse literature data sets. The steps we will outline include the definition of similarity used to determine nearest neighbors (NN), how we incorporate the NN activity landscape with a similarity-weighted root-mean-square distance (wRMSD) value, and how that value is then calibrated to generate an intuitive confidence metric for prospective application. Finally, we will illustrate the prospective performance of the approach on five proprietary models whose predictions and confidence metrics have been tracked for more than a year. PMID:23343412

Keefer, Christopher E; Kauffman, Gregory W; Gupta, Rishi Raj

2013-02-05

177

Peptide inhibitors of botulinum neurotoxin serotype A: design, inhibition, cocrystal structures, structure-activity relationship and pharmacophore modeling  

SciTech Connect

Clostridium botulinum neurotoxins are classified as Category A bioterrorism agents by the Centers for Disease Control and Prevention (CDC). The seven serotypes (A-G) of the botulinum neurotoxin, the causative agent of the disease botulism, block neurotransmitter release by specifically cleaving one of the three SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) proteins and induce flaccid paralysis. Using a structure-based drug-design approach, a number of peptide inhibitors were designed and their inhibitory activity against botulinum serotype A (BoNT/A) protease was determined. The most potent peptide, RRGF, inhibited BoNT/A protease with an IC{sub 50} of 0.9 {micro}M and a K{sub i} of 358 nM. High-resolution crystal structures of various peptide inhibitors in complex with the BoNT/A protease domain were also determined. Based on the inhibitory activities and the atomic interactions deduced from the cocrystal structures, the structure-activity relationship was analyzed and a pharmacophore model was developed. Unlike the currently available models, this pharmacophore model is based on a number of enzyme-inhibitor peptide cocrystal structures and improved the existing models significantly, incorporating new features.

Kumar G.; Swaminathan S.; Kumaran, D.; Ahmed, S. A.

2012-05-01

178

Structure-activity relationships for xenobiotic transport substrates and inhibitory ligands of P-glycoprotein.  

PubMed Central

The multixenobiotic resistance phenotype is characterized by the reduced accumulation of xenobiotics by cells or organisms due to increased efflux of the compounds by P-glycoprotein (P-gp) or related transporters. An extensive xenobiotic database, consisting primarily of pesticides, was utilized in this study to identify molecular characteristics that render a xenobiotic susceptible to transport by or inhibition of P-gp. Transport substrates were differentiated by several molecular size/shape parameters, lipophilicity, and hydrogen bonding potential. Electrostatic features differentiated inhibitory ligands from compounds not catagorized as transport substrates and that did no interact with P-gp. A two-tiered system was developed using the derived structure-activity relationships to identify P-gp transport substrates and inhibitory ligands. Prediction accuracy of the approach was 82%. We then validated the system using six additional pesticides of which tow were predicted to be P-gp inhibitors and four were predicted to be noninteractors, based upon the structure-activity analyses. Experimental determinations using cells transfected with the human MDR1 gene demonstrated that five of the six pesticides were properly catagorized by the structure-activity analyses (83% accuracy). Finally, structure-activity analyses revealed that among P-gp inhibitors, relative inhibitory potency can be predicted based upon the surface area or volume of the compound. These results demonstrate that P-gp transport substrates and inhibitory ligands can be distinguished using molecular characteristics. Molecular characteristics of transport substrates suggest that P-gp may function in the elimination of hydroxylated metabolites of xenobiotics. Images Figure 1. A Figure 1. B Figure 1. C Figure 1. D Figure 1. E Figure 1. F Figure 1. G Figure 1. H Figure 2. Figure 2. Figure 2. Figure 2. Figure 2. Figure 2. Figure 3. A Figure 3. B

Bain, L J; McLachlan, J B; LeBlanc, G A

1997-01-01

179

Introducing Spectral Structure Activity Relationship (S-SAR) Analysis. Application to Ecotoxicology  

PubMed Central

A novel quantitative structure-activity (property) relationship model, namely Spectral-SAR, is presented in an exclusive algebraic way replacing the old-fashioned multi-regression one. The actual S-SAR method interprets structural descriptors as vectors in a generic data space that is further mapped into a full orthogonal space by means of the Gram-Schmidt algorithm. Then, by coordinated transformation between the data and orthogonal spaces, the S-SAR equation is given under simple determinant form for any chemical-biological interactions under study. While proving to give the same analytical equation and correlation results with standard multivariate statistics, the actual S-SAR frame allows the introduction of the spectral norm as a valid substitute for the correlation factor, while also having the advantage to design the various related SAR models through the introduced “minimal spectral path” rule. An application is given performing a complete S-SAR analysis upon the Tetrahymena pyriformis ciliate species employing its reported eco-toxicity activities among relevant classes of xenobiotics. By representing the spectral norm of the endpoint models against the concerned structural coordinates, the obtained S-SAR endpoints hierarchy scheme opens the perspective to further design the ecotoxicological test batteries with organisms from different species.

Putz, Mihai V.; Lacrama, Ana-Maria

2007-01-01

180

Targeted Mutations of Bacillus anthracis Dihydrofolate Reductase Condense Complex Structure-Activity Relationships  

SciTech Connect

Several antifolates, including trimethoprim (TMP) and a series of propargyl-linked analogues, bind dihydrofolate reductase from Bacillus anthracis (BaDHFR) with lower affinity than is typical in other bacterial species. To guide lead optimization for BaDHFR, we explored a new approach to determine structure-activity relationships whereby the enzyme is altered and the analogues remain constant, essentially reversing the standard experimental design. Active site mutants of the enzyme, Ba(F96I)DHFR and Ba(Y102F)DHFR, were created and evaluated with enzyme inhibition assays and crystal structures. The affinities of the antifolates increase up to 60-fold with the Y102F mutant, suggesting that interactions with Tyr 102 are critical for affinity. Crystal structures of the enzymes bound to TMP and propargyl-linked inhibitors reveal the basis of TMP resistance and illuminate the influence of Tyr 102 on the lipophilic linker between the pyrimidine and aryl rings. Two new inhibitors test and validate these conclusions and show the value of the technique for providing new directions during lead optimization.

J Beierlein; N Karri; A Anderson

2011-12-31

181

Drug-receptor interaction-based quantitative structure-activity relationship of tetrahydroimidazodiazepinone  

NASA Astrophysics Data System (ADS)

Log P, solvent-accessible surface area (SASA), total energy, bond length, and bond strain of the most favorable H-bond formed between drug and receptor; and quantum chemical descriptor ?E nm‡-based quantitative structure-activity relationship (QSAR) study of tetrahydroimidazodiazepinone derivatives have been done. For QSAR study, the 3D modeling and geometry optimization of all the derivatives and receptor's amino acid have been carried out on CAChe software by applying semiempirical method using MOPAC 2002. Softness Calculator using semiempirical PM3 methods has done the atomic softness of every atom of the derivatives and receptor's amino acids. The biological activities of tetrahydroimidazodiazepinone derivatives have been taken from the literature. The predicted values of biological activity with the help of multiple linear regression analysis are close to observed activity. The cross-validation coefficient and correlation coefficient also indicate that the QSAR model is valuable. Regression analysis shows that hydrophobic interaction is predominant and made major contribution, whereas hydrogen bonding and polar interactions help in proper orientation of the compound (or its functional groups) to make maximum interaction. With the help of these descriptors, prediction of the biological activity of new derivative is possible.

Sahu, V. K.; Khan, A. K. R.; Singh, R. K.; Singh, P. P.

182

Structure-hepatoprotective activity relationship study of sesquiterpene lactones: A QSAR analysis  

NASA Astrophysics Data System (ADS)

This study has been carried out using quantitative structure-activity relationship analysis (QSAR) for 22 sesquiterpene lactones to correlate and predict their hepatoprotective activity. Sesquiterpenoids, the largest class of terpenoids, are a widespread group of substances occurring in various plant organisms. QSAR analysis was carried out using methods such as genetic algorithm for variables selection among generated and calculated descriptors and multiple linear regression analysis. Quantum-chemical calculations have been performed by density functional theory at B3LYP/6-311G(d, p) level for evaluation of electronic properties using reference geometries optimized by semi-empirical AM1 approach. Three models describing hepatoprotective activity values for series of sesquiterpene lactones are proposed. The obtained models are useful for description of sesquiterpene lactones hepatoprotective activity and can be used to estimate the hepatoprotective activity of new substituted sesquiterpene lactones. The models obtained in our study show not only statistical significance, but also good predictive ability. The estimated predictive ability (rtest2) of these models lies within 0.942-0.969.

Paukku, Yuliya; Rasulev, Bakhtiyor; Syrov, Vladimir; Khushbaktova, Zainab; Leszczynski, Jerzy

183

Structure-activity relationship of memapsin 2: implications on physiological functions and Alzheimer's disease.  

PubMed

Memapsin 2 (BACE1, ?-secretase), a membrane aspartic protease, functions in the cleavage of the type I transmembrane protein, ?-amyloid precursor protein (APP), leading to the production of amyloid ? (A?) in the brain. Since A? is closely associated with the pathogenesis of Alzheimer's disease, understanding the biological function, particularly the catalytic activities of memapsin 2, would assist in a better understanding of the disease and the development of its inhibitors. The transmembrane and cytosolic domains of memapsin 2 function in cellular transport and localization, which are important regulatory mechanisms for its activity. The catalytic ectodomain contains a long substrate cleft that is responsible for substrate recognition, specificity, and peptide bond hydrolysis. The substrate cleft accommodates 11 residues of the substrate in separate binding subsites. Besides APP, a number of membrane proteins have been reported to be substrates of memapsin 2. The elucidation for the specificity of these subsites and the amino acid sequences surrounding the memapsin 2 cleavage site in these proteins has led to the establishment of a predictive model that can quantitatively estimate the efficiency of cleavage for any potential substrates. Such tools may be employed for future studies of memapsin 2 about its biological function. Herein, we review the current knowledge on the structure-function relationship of memapsin 2 and its relationship in the biological function. PMID:23676825

Li, Xiaoman; Hong, Lin; Coughlan, Kathleen; Wang, Liang; Cao, Liu; Tang, Jordan

2013-05-15

184

Quantitative structure-activity relationship analysis of a series of human renal organic anion transporter inhibitors.  

PubMed

Organic anion transporters (OATs) have been proved to play important roles in the membrane transport of numerous potentially toxic xenobiotics, drugs, and endogenous metabolites. In general, OATs substrates can compete with one another for the transporter to mutually decrease renal secretion and thus delay the clearance and prolong the duration of action of each compound. Such interactions have the potential to bring about adverse outcomes for clinical cases. Therefore, it is very important to assess the molecular bioactivity to inhibit OATs during the development of new drugs and co-administration. In this work, the relationships between 45 chemicals and their corresponding hOAT1 and hOAT3 inhibitory activities were analyzed. The quantitative structure-activity relationship (QSAR) model was developed by genetic algorithm and multiple linear regression method. The predictive power of the proposed model was strictly evaluated, and the applicability domain was also defined. The proposed models were robust and satisfactory and could provide a feasible and effective tool for hOAT1 or hOAT3 inhibitor screening. PMID:22829314

Wei, Yuhui; Xi, Lili; Yao, Xiaojun; Li, Jiazhong; Wu, Xinan

2012-07-24

185

Similarity boosted quantitative structure-activity relationship--a systematic study of enhancing structural descriptors by molecular similarity.  

PubMed

The concept of molecular similarity is one of the most central in the fields of predictive toxicology and quantitative structure-activity relationship (QSAR) research. Many toxicological responses result from a multimechanistic process and, consequently, structural diversity among the active compounds is likely. Combining this knowledge, we introduce similarity boosted QSAR modeling, where we calculate molecular descriptors using similarities with respect to representative reference compounds to aid a statistical learning algorithm in distinguishing between different structural classes. We present three approaches for the selection of reference compounds, one by literature search and two by clustering. Our experimental evaluation on seven publicly available data sets shows that the similarity descriptors used on their own perform quite well compared to structural descriptors. We show that the combination of similarity and structural descriptors enhances the performance and that a simple stacking approach is able to use the complementary information encoded by the different descriptor sets to further improve predictive results. All software necessary for our experiments is available within the cheminformatics software framework AZOrange. PMID:23489025

Girschick, Tobias; Almeida, Pedro R; Kramer, Stefan; Stålring, Jonna

2013-04-29

186

Synthesis and structure–activity relationship studies in peripheral benzodiazepine receptor ligands related to alpidem  

Microsoft Academic Search

The exploration of the structure–affinity relationships concerning a new class of peripheral benzodiazepine receptor (PBR) ligands related to alpidem has been pursued in order to evaluate the consistency of the structure–affinity relationships among different classes (and subclasses) of PBR ligands. The target amide derivatives were prepared following a previously published procedure based on the condensation of pyrrolo[3,4-b]quinoline derivatives 11a,b with

Andrea Cappelli; Germano Giuliani; Salvatore Valenti; Maurizio Anzini; Salvatore Vomero; Gianluca Giorgi; Cristiana Sogliano; Elisabetta Maciocco; Giovanni Biggio; Alessandra Concas

2008-01-01

187

Amyloid-? probes: Review of structure-activity and brain-kinetics relationships.  

PubMed

The number of people suffering from Alzheimer's disease (AD) is expected to increase dramatically in the coming years, placing a huge burden on society. Current treatments for AD leave much to be desired, and numerous research efforts around the globe are focused on developing improved therapeutics. In addition, current diagnostic tools for AD rely largely on subjective cognitive assessment rather than on identification of pathophysiological changes associated with disease onset and progression. These facts have led to numerous efforts to develop chemical probes to detect pathophysiological hallmarks of AD, such as amyloid-? plaques, for diagnosis and monitoring of therapeutic efficacy. This review provides a survey of chemical probes developed to date for AD with emphasis on synthetic methodologies and structure-activity relationships with regards to affinity for target and brain kinetics. Several probes discussed herein show particularly promising results and will be of immense value moving forward in the fight against AD. PMID:23766818

Eckroat, Todd J; Mayhoub, Abdelrahman S; Garneau-Tsodikova, Sylvie

2013-05-28

188

Structure-activity relationship of gramine derivatives in Ca(2+) release from sarcoplasmic reticulum.  

PubMed

5,6-Dibromo-1,2-dimethylgramine evoked Ca(2+) release from skeletal muscle sarcoplasmic reticulum through ryanodine receptors in a concentration-dependent manner with an EC(50) of 22.2 microM. Since the EC(50) of caffeine was 0.885 mM, 5,6-dibromo-1,2-dimethylgramine was 40 times more sensitive than caffeine. Among 14 gramine derivatives having different substituents at N-1, C-2, C-5 or C-6 of the indole skeleton, we found that five derivatives were effective. Study of the structure-activity relationship for Ca(2+) release indicated that 1-methylation and/or both 5- and 6-bromination are important for Ca(2+) release. Thus, gramine derivatives are useful tools for the investigation of Ca(2+) release from sarcoplasmic reticulum. PMID:10528147

Nakahata, N; Harada, Y; Tsuji, M; Kon-ya, K; Shizuri, Y; Ohizumi, Y

1999-10-01

189

Amyloid-? probes: Review of structure-activity and brain-kinetics relationships  

PubMed Central

Summary The number of people suffering from Alzheimer’s disease (AD) is expected to increase dramatically in the coming years, placing a huge burden on society. Current treatments for AD leave much to be desired, and numerous research efforts around the globe are focused on developing improved therapeutics. In addition, current diagnostic tools for AD rely largely on subjective cognitive assessment rather than on identification of pathophysiological changes associated with disease onset and progression. These facts have led to numerous efforts to develop chemical probes to detect pathophysiological hallmarks of AD, such as amyloid-? plaques, for diagnosis and monitoring of therapeutic efficacy. This review provides a survey of chemical probes developed to date for AD with emphasis on synthetic methodologies and structure–activity relationships with regards to affinity for target and brain kinetics. Several probes discussed herein show particularly promising results and will be of immense value moving forward in the fight against AD.

Eckroat, Todd J; Mayhoub, Abdelrahman S

2013-01-01

190

Understanding the structure-function relationship between FGF19 and its mitogenic and metabolic activities.  

PubMed

FGF19 differs from the classical FGFs in that it has a much-reduced heparan sulfate proteoglycan binding affinity that allows it to act as endocrine hormone. Although FGF19 regulates several different metabolic activities, it still activates downstream signaling pathways through FGF receptors, in a similar manner to that seen in classical FGFs. Aberrant FGF signaling has been implicated in tumor development, and mouse models have confirmed that FGF19 has the potential to induce hepatocellular carcinoma. Treatment with anti-FGF19 antibody suppressed tumor progression in both FGF19 transgenic mice and colon cancer cell xenograft models. FGFR4, the predominant FGF receptor expressed in the liver, may play an important role in FGF19-mediated tumorigenesis. This review reports the current advances in understanding the structure-function relationship between FGF19 and its interactions with FGFRs, its physiological activities, and its differences from FGF21. The review also discusses strategies to separate the mitogenic and metabolic activities for the development of potential therapeutic molecules based on FGF19. PMID:22396171

Wu, Xinle; Li, Yang

2012-01-01

191

Immunostimulation by Synthetic Lipopeptide-Based Vaccine Candidates: Structure-Activity Relationships  

PubMed Central

Peptide-based vaccines offer several advantages over conventional whole organism or protein approaches by offering improved purity and specificity in inducing immune response. However, peptides alone are generally non-immunogenic. Concerns remain about the toxicity of adjuvants which are critical for immunogenicity of synthetic peptides. The use of lipopeptides in peptide vaccines is currently under intensive investigation because potent immune responses can be generated without the use of adjuvant (thus are self-adjuvanting). Several lipopeptides derived from microbial origin, and their synthetic versions or simpler fatty acid moieties impart this self-adjuvanting activity by signaling via Toll-like receptor 2 (TLR2). Engagement of this innate immune receptor on antigen-presenting cell leads to the initiation and development of potent immune responses. Therefore optimization of lipopeptides to enhance TLR2-mediated activation is a promising strategy for vaccine development. Considerable structure-activity relationships that determine TLR2 binding and consequent stimulation of innate immune responses have been investigated for a range of lipopeptides. In this mini review we address the development of lipopeptide vaccines, mechanism of TLR2 recognition, and immune activation. An overview is provided of the best studied lipopeptide vaccine systems.

Zaman, Mehfuz; Toth, Istvan

2013-01-01

192

Quantifying the fingerprint descriptor dependence of structure-activity relationship information on a large scale.  

PubMed

It is well-known that different molecular representations, e.g., graphs, numerical descriptors, fingerprints, or 3D models, change the numerical results of molecular similarity calculations. Because the assessment of structure-activity relationships (SARs) requires similarity and potency comparisons of active compounds, this representation dependence inevitably also affects SAR analysis. But to what extent? How exactly does SAR information change when alternative fingerprints are used as descriptors? What is the proportion of active compounds with substantial changes in SAR information induced by different fingerprints? To provide answers to these questions, we have quantified changes in SAR information across many different compound classes using six different fingerprints. SAR profiling was carried out on 128 target-based data sets comprising more than 60?000 compounds with high-confidence activity annotations. A numerical measure of SAR discontinuity was applied to assess SAR information on a per compound basis. For ?70% of all test compounds, changes in SAR characteristics were detected when different fingerprints were used as molecular representations. Moreover, the SAR phenotype of ?30% of the compounds changed, and distinct fingerprint-dependent local SAR environments were detected. The fingerprints we compared were found to generate SAR models that were essentially not comparable. Atom environment and pharmacophore fingerprints produced the largest differences in compound-associated SAR information. Taken together, the results of our systematic analysis reveal larger fingerprint-dependent changes in compound-associated SAR information than would have been anticipated. PMID:23968259

Dimova, Dilyana; Stumpfe, Dagmar; Bajorath, Jürgen

2013-09-06

193

Disubstituted amino-, nitroso-, and nitrofluorenes: a physicochemical basis for structure-activity relationships in Salmonella typhimurium  

SciTech Connect

Twenty-nine derivatives of fluorene were tested for mutagenic potency in four strains of Salmonella typhimurium with and/or without S9 microsomal activation. The effects of a second functional group on the mutagenic activity of an amino-nitroso-, and nitrofluorene were correlated with its physical and chemical properties. When the functional group is conjugated by resonance, both inductive and resonance effects are determinants of mutagenic potency. Electron-withdrawing groups such as the halogens (F, Cl, Br, and I), nitro, nitroso, and cyano at C-7 increased the mutagenic potency of 2-nitrofluorene. Acetylation of a hydroxy or an amino group at C-7 increased the mutagenic potency of 2-nitrofluorene. The physical properties of a second functional group are expected to exert their effect(s) at three points in the metabolic activation of 2,7-disubstituted fluorene derivatives: 1) initial reduction of the nitro group (redox effect), 2) stabilization of the hydroxylamine (inductive effect), and 3) stabilization/destabilization of the nitrenium ion (resonance and inductive effects). The relationships between the physical properties of a second functional group and their effects on biological activities of nitro- and aminofluorenes in the Ames Salmonella assay may be of predictive value in a first approximation of both the mutagenic and carcinogenic potency of chemicals with comparable structures such as fluoranthene and biphenyl.

Vance, W.A.; Wang, Y.Y.; Okamoto, H.S.

1987-01-01

194

Structure-activity relationships for perfluoroalkane-induced in vitro interference with rat liver mitochondrial respiration.  

PubMed

Perfluorinated alkyl acids (PFAAs) represent a broad class of commercial products designed primarily for the coatings industry. However, detection of residues globally in a variety of species led to the discontinuation of production in the U.S. Although PFAAs cause activation of the PPAR? and CAR nuclear receptors, interference with mitochondrial bioenergetics has been implicated as an alternative mechanism of cytotoxicity. Although the mechanisms by which the eight carbon chain PFAAs interfere with mitochondrial bioenergetics are fairly well described, the activities of the more highly substituted or shorter chain PFAAs are far less well characterized. The current investigation was designed to explore structure-activity relationships by which PFAAs interfere with mitochondrial respiration in vitro. Freshly isolated rat liver mitochondria were incubated with one of 16 different PFAAs, including perfluorinated carboxylic, acetic, and sulfonic acids, sulfonamides and sulfamido acetates, and alcohols. The effect on mitochondrial respiration was measured at five concentrations and dose-response curves were generated to describe the effects on state 3 and 4 respiration and respiratory control. With the exception of PFOS, all PFAAs at sufficiently high concentrations (>20?M) stimulated state 4 and inhibited state 3 respiration. Stimulation of state 4 respiration was most pronounced for the carboxylic acids and the sulfonamides, which supports prior evidence that the perfluorinated carboxylic and acetic acids induce the mitochondrial permeability transition, whereas the sulfonamides are protonophoric uncouplers of oxidative phosphorylation. In both cases, potency increased with increasing carbon number, with a prominent inflection point between the six and eight carbon congeners. The results provide a foundation for classifying PFAAs according to specific modes of mitochondrial activity and, in combination with toxicokinetic considerations, establishing structure-activity-based boundaries for initial estimates of risk for noncancer endpoints for PFAAs for which minimal in vivo toxicity testing currently exists. PMID:23954199

Wallace, K B; Kissling, G E; Melnick, R L; Blystone, C R

2013-08-14

195

Olfactory sensitivity and odor structure-activity relationships for aliphatic carboxylic acids in CD-1 mice.  

PubMed

Using a conditioning paradigm, the olfactory sensitivity of CD-1 mice for a homologous series of aliphatic n-carboxylic acids (ethanoic acid to n-octanoic acid) and several of their isomeric forms was investigated. With all 14 odorants, the animals significantly discriminated concentrations as low as 0.03 ppm (parts per million) from the solvent, and with four odorants the best-scoring animals even detected concentrations as low as 3 ppt (parts per trillion). Analysis of odor structure-activity relationships showed that the correlation between olfactory detection thresholds of the mice for the unbranched carboxylic acids and carbon chain length can best be described as a U-shaped function with the lowest threshold values at n-butanoic acid. A significant positive correlation between olfactory detection thresholds and carbon chain length of the carboxylic acids with their branching next to the functional carboxyl group was found. In contrast, no such correlation was found for carboxylic acids with their branching at the distal end of the carbon chain relative to the functional carboxyl group. Finally, a significant correlation was found between olfactory detection thresholds and the position of the branching of the carboxylic acids. Across-species comparisons suggest that mice are more sensitive for short-chained (C(2) to C(4)) aliphatic n-carboxylic acids than other mammalian species, but not for longer-chained ones (C(5) to C(8)). Further comparisons suggest that odor structure-activity relationships are both substance class- and species-specific. PMID:22479594

Can Güven, Selçuk; Laska, Matthias

2012-03-30

196

Molecular-orbital analysis of the electronic structure and determination of quantitative structure-activity and structure-toxicity relationships for water-soluble ionol derivatives  

SciTech Connect

In this paper the authors attempt to establish a quantitative relationship between experimental data on antitumor activity and the toxicity of ionol and its derivatives on the one hand, and on the other hand the electronic structure parameters of the compounds obtained as a result of the quantum chemical calculation.

Bushelev, S.N.

1985-08-01

197

Structure-activity relationship analysis of cytotoxic cyanoguanidines: selection of CHS 828 as candidate drug  

PubMed Central

Background N-(6-(4-chlorophenoxy)hexyl)-N'-cyano-N''-4-pyridyl guanidine) (CHS 828) is the first candidate drug from a novel group of anti-tumour agents – the pyridyl cyanoguanidines, shown to be potent compounds interfering with cellular metabolism (inhibition of nicotinamide phosphoribosyl transferase) and NF-?B signalling. Substituted cyanoguanidines are also found in anti-hypertensive agents such as the potassium channel opener pinacidil (N-cyano-N'-(4-pyridyl)-N''-(1,2,2-trimethylpropyl)guanidine) and histamine-II receptor antagonists (e.g. cimetidine, N-cyano-N'-methyl-N''-[2-[[(5-methylimidazol-4-yl]methyl]thio]ethyl)guanidine). In animal studies, CHS 828 has shown very promising activity, and phase I and II studies resulted in further development of a with a water soluble prodrug. Findings To study the structural requirements for cyanoguanidine cytotoxicity a set of 19 analogues were synthesized. The cytotoxic effects were then studied in ten cell lines selected for different origins and mechanisms of resistance, using the fluorometric microculture cytotoxicity assay (FMCA). The compounds showed varying cytotoxic activity even though the dose-response curves for some analogues were very shallow. Pinacidil and cimetidine were found to be non-toxic in all ten cell lines. Starting with cyanoguanidine as the crucial core it was shown that 4-pyridyl substitution was more efficient than was 3-pyridyl substitution. The 4-pyridyl cyanoguanidine moiety should be linked by an alkyl chain, optimally a hexyl, heptyl or octyl chain, to a bulky end group. The exact composition of this end group did not seem to be of crucial importance; when the end group was a mono-substituted phenyl ring it was shown that the preferred position was 4-substitution, followed by 3- and, finally, 2-substitution as the least active. Whether the substituent was a chloro, nitro or methoxy substituent seemed to be of minor importance. Finally, the activity patterns in the ten cell lines were compared. Substances with similar structures correlated well, whilst substances with large differences in molecular structure demonstrated lower correlation coefficients. Conclusion According to this structure-activity relationship (SAR) study, CHS 828 meets the requirements for optimal cytotoxic activity for this class of compounds.

Lovborg, Henrik; Burman, Robert; Gullbo, Joachim

2009-01-01

198

Adapted Transfer of Distance Measures for Quantitative Structure-Activity Relationships  

NASA Astrophysics Data System (ADS)

Quantitative structure-activity relationships (QSARs) are regression models relating chemical structure to biological activity. Such models allow to make predictions for toxicologically or pharmacologically relevant endpoints, which constitute the target outcomes of trials or experiments. The task is often tackled by instance-based methods (like k-nearest neighbors), which are all based on the notion of chemical (dis-)similarity. Our starting point is the observation by Raymond and Willett that the two big families of chemical distance measures, fingerprint-based and maximum common subgaph based measures, provide orthogonal information about chemical similarity. The paper presents a novel method for finding suitable combinations of them, called adapted transfer, which adapts a distance measure learned on another, related dataset to a given dataset. Adapted transfer thus combines distance learning and transfer learning in a novel manner. In a set of experiments, we compare adapted transfer with distance learning on the target dataset itself and inductive transfer without adaptations. In our experiments, we visualize the performance of the methods by learning curves (i.e., depending on training set size) and present a quantitative comparison for 10% and 100% of the maximum training set size.

Rückert, Ulrich; Girschick, Tobias; Buchwald, Fabian; Kramer, Stefan

199

Structure-activity relationship study on the binding of PBDEs with thyroxine transport proteins.  

PubMed

Molecular docking and three-dimensional quantitative structure-activity relationships (3D-QSAR) were used to develop models to predict binding affinity of polybrominated diphenyl ether (PBDE) compounds to the human transthyretin (TTR). Based on the molecular conformations derived from the molecular docking, predictive comparative molecular similarity indices analysis (CoMSIA) models were developed. The results of CoMSIA models were as follows: leave-one-out (LOO) cross-validated squared coefficient q² (LOO)?=?0.827 (full model, for all 28 compounds); q² (LOO)?=?0.752 (split model, for 22 compounds in the training set); leave-many-out (LMO) cross-validated squared coefficient q² (LMO, two groups)?=?0.723?±?0.100 (full model, for all 28 compounds); q² (LMO, five groups)?=?0.795?±?0.030 (full model, for all 28 compounds); and the predictive squared correlation coefficient r²(pred) ?=?0.928 (for six compounds in the test set). The developed CoMSIA models can be used to infer the activities of compounds with similar structural characteristics. In addition, the interaction mechanism between hydroxylated polybrominated diphenyl ethers (HO-PBDEs) and the TTR was explored. Hydrogen bonding with amino acid residues Asp74, Ala29, and Asn27 may be an important determinant for HO-PBDEs binding to TTR. Among them, forming hydrogen bonds with amino acid residues Asp74 might exert a more important function. PMID:21842493

Yang, Weihua; Shen, Shide; Mu, Lailong; Yu, Hongxia

2011-09-27

200

Synthesis and structure-activity relationships of the halovirs, antiviral natural products from a marine-derived fungus.  

PubMed

The halovirs are linear, lipophilic peptides produced by a marine-derived fungus of the genus Scytalidium. We recently reported that these molecules possess potent in vitro activity against the herpes simplex viruses 1 and 2. Here we present structure-activity relationships defining key structural elements for optimal viral inhibition. Results demonstrate that an N(alpha)-acyl chain of at least 14 carbons and an Aib-Pro dipeptide are critical for maintaining the antiviral activity. PMID:15336272

Rowley, David C; Kelly, Sara; Jensen, Paul; Fenical, William

2004-09-15

201

Quantitative structure-activity relationship models for ready biodegradability of chemicals.  

PubMed

The European REACH regulation requires information on ready biodegradation, which is a screening test to assess the biodegradability of chemicals. At the same time REACH encourages the use of alternatives to animal testing which includes predictions from quantitative structure-activity relationship (QSAR) models. The aim of this study was to build QSAR models to predict ready biodegradation of chemicals by using different modeling methods and types of molecular descriptors. Particular attention was given to data screening and validation procedures in order to build predictive models. Experimental values of 1055 chemicals were collected from the webpage of the National Institute of Technology and Evaluation of Japan (NITE): 837 and 218 molecules were used for calibration and testing purposes, respectively. In addition, models were further evaluated using an external validation set consisting of 670 molecules. Classification models were produced in order to discriminate biodegradable and nonbiodegradable chemicals by means of different mathematical methods: k nearest neighbors, partial least squares discriminant analysis, and support vector machines, as well as their consensus models. The proposed models and the derived consensus analysis demonstrated good classification performances with respect to already published QSAR models on biodegradation. Relationships between the molecular descriptors selected in each QSAR model and biodegradability were evaluated. PMID:23469921

Mansouri, Kamel; Ringsted, Tine; Ballabio, Davide; Todeschini, Roberto; Consonni, Viviana

2013-03-27

202

Quantitative structure-activity relationship for aromatic hydrocarbons on freshwater fish.  

PubMed

A quantitative structure-activity relationship (QSAR) was determined, according to Hansch's approach. The acute toxicity of nine aromatic hydrocarbons (benzene, toluene, ethylbenzene, o-xylene, m-xylene, p-xylene, isopropylbenzene, n-propylbenzene, butylbenzene) was evaluated in an Argentinean freshwater fish species. Solubility, molecular weight, and the octanol-water coefficient of partition (K(ow)) were taken as macroscopic molecular descriptors. Slopes obtained from regression analysis were similar with respect to those of the standard fish, Pimephales promelas. A potential nonpolar narcosis power (NP) concept was defined on the basis of the mode of toxic action of the assayed chemicals. Following Ferguson's principle and the critical volume doctrine for nonpolar narcosis, NP was defined as log MW*K(ow). Experimental data fitted better than regression analysis did only with log K(ow). NP improves the quantitative relationship between nonpolar narcotic compounds and their toxicity. It was more suitable to describe the physiological aspects relative to the mode of action of the chemicals assayed. PMID:15327885

Di Marzio, Walter; Saenz, Maria Elena

2004-10-01

203

Quantitative Structure-Activity Relationship Studies of 4-Imidazolyl- 1,4-dihydropyridines as Calcium Channel Blockers  

PubMed Central

Objective(s): The structure- activity relationship of a series of 36 molecules, showing L-type calcium channel blocking was studied using a QSAR (quantitative structure–activity relationship) method. Materials and Methods: Structures were optimized by the semi-empirical AM1 quantum-chemical method which was also used to find structure-calcium channel blocking activity trends. Several types of descriptors, including electrotopological, structural and thermodynamics were used to derive a quantitative relationship between L-type calcium channel blocking activity and structural properties. The developed QSAR model contributed to a mechanistic understanding of the investigated biological effects. Results: Multiple linear regressions (MLR) was employed to model the relationships between molecular descriptors and biological activities of molecules using stepwise method and genetic algorithm as variable selection tools. The accuracy of the proposed MLR model was illustrated using cross-validation, and Y-randomisation -as the evaluation techniques. Conclusion: The predictive ability of the model was found to be satisfactory and could be used for designing a similar group of 1,4- dihydropyridines , based on a pyridine structure core which can block calcium channels.

Hadizadeh, Farzin; Vahdani, Saadat; Jafarpour, Mehrnaz

2013-01-01

204

Quantitative Structure-Activity Relationship Studies of 4-Imidazolyl- 1,4-dihydropyridines as Calcium Channel Blockers.  

PubMed

Objective(s): The structure- activity relationship of a series of 36 molecules, showing L-type calcium channel blocking was studied using a QSAR (quantitative structure-activity relationship) method. Materials and Methods: Structures were optimized by the semi-empirical AM1 quantum-chemical method which was also used to find structure-calcium channel blocking activity trends. Several types of descriptors, including electrotopological, structural and thermodynamics were used to derive a quantitative relationship between L-type calcium channel blocking activity and structural properties. The developed QSAR model contributed to a mechanistic understanding of the investigated biological effects. Results: Multiple linear regressions (MLR) was employed to model the relationships between molecular descriptors and biological activities of molecules using stepwise method and genetic algorithm as variable selection tools. The accuracy of the proposed MLR model was illustrated using cross-validation, and Y-randomisation -as the evaluation techniques. Conclusion: The predictive ability of the model was found to be satisfactory and could be used for designing a similar group of 1,4- dihydropyridines , based on a pyridine structure core which can block calcium channels. PMID:24106595

Hadizadeh, Farzin; Vahdani, Saadat; Jafarpour, Mehrnaz

2013-08-01

205

Structure-activity relationships for novel drug precursor N-substituted-6-acylbenzothiazolon derivatives: A theoretical approach  

NASA Astrophysics Data System (ADS)

Structure-activity relationships for novel drug precursor 6-acylbenzothiazolon derivatives are researched.Vm, MR, ?, EA, EHOMO - ELUMO (?E), HOF, ?, ?, S and ? parameters give good correlations with log P.The electronic structures of 6-acylbenzothiazolon derivatives have been expounded.Molecular polarity, hydrophilic character and dipole moment show the same trend.

S?d?r, Yadigar Gülseven; S?d?r, ?sa

2013-08-01

206

Computational structure-activity relationship analysis of small-molecule agonists for human formyl peptide receptors.  

PubMed

N-formyl peptide receptors (FPRs) are important in host defense. Because of the potential for FPRs as therapeutic targets, recent efforts have focused on identification of non-peptide agonists for two FPR subtypes, FPR1 and FPR2. Given that a number of specific small-molecule agonists have recently been identified, we hypothesized that computational structure-activity relationship (SAR) analysis of these molecules could provide new information regarding molecular features required for activity. We used a training set of 71 compounds, including 10 FPR1-specific agonists, 36 FPR2-specific agonists, and 25 non-active analogs. A sequence of (1) one-way analysis of variance selection, (2) cluster analysis, (3) linear discriminant analysis, and (4) classification tree analysis led to the derivation of SAR rules with high (95.8%) accuracy for correct classification of compounds. These SAR rules revealed key features distinguishing FPR1 versus FPR2 agonists. To verify predictive ability, we evaluated a test set of 17 additional FPR agonists, and found that the majority of these agonists (>94%) were classified correctly as agonists. This study represents the first successful application of classification tree methodology based on atom pairs to SAR analysis of FPR agonists. Importantly, these SAR rules represent a relatively simple classification approach for virtual screening of FPR1/FPR2 agonists. PMID:20870313

Khlebnikov, Andrei I; Schepetkin, Igor A; Quinn, Mark T

2010-09-15

207

Computational Structure-activity Relationship Analysis of Small-Molecule Agonists for Human Formyl Peptide Receptors  

PubMed Central

N-formyl peptide receptors (FPR) are important in host defense. Because of the potential for FPRs as therapeutic targets, recent efforts have focused on identification of non-peptide agonists for two FPR subtypes, FPR1 and FPR2. Given that a number of specific small molecule agonists have recently been identified, we hypothesized that computational structure-activity relationship (SAR) analysis of these molecules could provide new information regarding molecular features required for activity. We used a training set of 71 compounds, including 10 FPR1-specific agonists, 36 FPR2-specific agonists, and 25 non-active analogs. A sequence of (1) one-way analysis of variance selection, (2) cluster analysis, (3) linear discriminant analysis, and (4) classification tree analysis led to the derivation of SAR rules with high (95.8%) accuracy for correct classification of compounds. These SAR rules revealed key features distinguishing FPR1 versus FPR2 agonists. To verify predictive ability, we evaluated a test set of 17 additional FPR agonists, and found that the majority of these agonists (>94%) were classified correctly as agonists. This study represents the first successful application of classification tree methodology based on atom pairs to SAR analysis of FPR agonists. Importantly, these SAR rules represent a relatively simple classification approach for virtual screening of FPR1/FPR2 agonists.

Khlebnikov, Andrei I.; Schepetkin, Igor A; Quinn, Mark T.

2010-01-01

208

The Relationships Between Biological Activities and Structure of Flavan-3-Ols  

PubMed Central

Flavan-3-ols are involved in multiple metabolic pathways that induce inhibition of cell proliferation. We studied the structure-activity relationship of gallic acid (GA) and four flavan-3-ols: epigallocatechin gallate (EGCG), epigallocatechin (EGC), catechin (C), and epicatechin (EC). We measured the cell viability by the MTT assay and we determined the concentration of testing compound required to reduce cell viability by 50% (IC50). All tested compounds showed a dose-dependent and time-dependent inhibitory antiproliferative effect on Hs578T cells; IC50 values varying from the 15.81 to 326.8 ?M. Intracellular ROS (reactive oxygen species) were quantified using a fluorescent probe 2?,7?-dichlorofluorescin diacetate (DCFH-DA). Only the treatment with 10 ?M EGC and EGCG was able to induce a significant decrease of ROS concentration and increased levels of ROS were registered for 100 ?M EGCG, EGC and GA. Flavans-3-ols and GA induced apoptosis in a dose- and time-dependent manner, which indicated that the induction of apoptosis mediated their cytotoxic activity at least partially. The galloylated catechins have shown a stronger antiproliferative activity and apoptotic effect than the one produced by non galloylated catechins. The galloylated flavan-3-ols are potential therapeutic agents for patients with triple negative breast cancer via induction of apoptosis.

Braicu, Cornelia; Pilecki, Valentina; Balacescu, Ovidiu; Irimie, Alexandru; Berindan Neagoe, Ioana

2011-01-01

209

Structure–activity relationship studies on unifiram (DM232) and sunifiram (DM235), two novel and potent cognition enhancing drugs  

Microsoft Academic Search

Structure–activity relationships on two novel potent cognition enhancing drugs, unifiram (DM232, 1) and sunifiram (DM235, 2), are reported. Although none of the compounds synthesised reached the potency of the parent drugs, some fairly active compounds have been identified that may represent new leads to develop other cognition enhancing drugs. An interesting result of this research is the identification of two

Serena Scapecchi; Elisabetta Martini; Dina Manetti; Carla Ghelardini; Cecilia Martelli; Silvia Dei; Nicoletta Galeotti; Luca Guandalini; Maria Novella Romanelli; Elisabetta Teodori

2004-01-01

210

Structure-activity Relationship Analysis of N-Benzoylpyrazoles for Elastase Inhibitory Activity: A Simplified Approach Using Atom Pair Descriptors  

PubMed Central

Previously, we utilized high throughput screening of a chemical diversity library to identify potent inhibitors of human neutrophil elastase and found that many of these compounds had N-benzoylpyrazole core structures. We also found individual ring substituents had significant impact on elastase inhibitory activity and compound stability. In the present study, we utilized computational structure–activity relationship (SAR) analysis of a series of 53 N-benzoylpyrazole derivatives to further optimize these lead molecules. We present an improved approach to SAR methodology based on atom pair descriptors in combination with 2-dimentional (2D) molecular descriptors. This approach utilizes the rich representation of chemical structure and leads to SAR analysis that is both accurate and intuitively easy to understand. A sequence of ANOVA, linear discriminant, and binary classification tree analyses of the molecular descriptors led to the derivation of SAR rule-based algorithms. These rules revealed that the main factors influencing elastase inhibitory activity of N-benzoylpyrazole molecules were the presence of methyl groups in the pyrazole moiety and ortho-substituents in the benzoyl radical. Furthermore, our data showed that physicochemical characteristics (energy of frontier molecular orbitals, molar refraction, lipophilicity) were not necessary for achieving good SAR, as comparable quality of SAR classification was obtained with atom pairs and 2D descriptors only. This simplified SAR approach may be useful to qualitative SAR recognition problems in a variety of data sets.

Khlebnikov, Andrei I.; Schepetkin, Igor A.; Quinn, Mark T.

2008-01-01

211

Tyrosinase inhibitory effect of benzoic acid derivatives and their structure-activity relationships.  

PubMed

A series of benzoic acid derivatives 1-10 have been synthesised by two different methods. Compounds 1-6 were synthesised by a facile procedure for esterification using N,N'-dicyclohexylcarbodiimide (DCC) as a coupling agent, methylene chloride as a solvent system and dimethylaminopyridine (DMAP). While 7-10 were synthesised by converting benzoic acid into benzoyl chloride by treating with thionyl chloride in the presence of benzene and performing a further reaction with amine in dried benzene. The structures of all the synthesised derivatives of benzoic acid (1-10) were assigned on the basis of extensive NMR studies. All of them showed inhibitory potential against tyrosinase. Among them, compound 7 was found to be the most potent (1.09 ?M) when compared with the standard tyrosinase inhibitors of kojic acid (16.67 ?M) and L-mimosine (3.68 ?M). Finally in this paper, we have discussed the structure-activity relationships of the synthesised molecules. PMID:20476840

Khan, Sher Bahadar; Hassan Khan, Mahmud Tareq; Jang, Eui Sung; Akhtar, Kalsoom; Seo, Jongchul; Han, Haksoo

2010-05-17

212

Inhibitory effects of flavonoids on phosphodiesterase isozymes from guinea pig and their structure-activity relationships.  

PubMed

The structure-activity relationships of flavonoids with regard to their inhibitory effects on phosphodiesterase (PDE) isozymes are little known. The activities of PDE1-5 were measured by a two-step procedure using cAMP with [(3)H]-cAMP or cGMP with [(3)H]-cGMP as substrates. In the present results, PDE1, 5, 2, and 4 isozymes were partially purified from guinea pig lungs in that order, and PDE3 was from the heart. The IC(50) values of PDE1-5 were greater than those reported previously for the reference drugs, vinpocetin, EHNA, milrinone, Ro 20-1724, and zaprinast, by 5-, 5-, 7-, 5-, and 3-fold, respectively. As shown in Table 2, luteolin revealed non-selective inhibition of PDE1-5 with IC(50) values in a range of 10-20 microM, as did genistein except with a low potency on PDE5. Daidzein, an inactive analogue of genistein in tyrosine kinase inhibition, showed selective inhibition of PDE3 with an IC(50) value of around 30 microM, as did eriodictyol with an IC(50) value of around 50 microM. Hesperetin and prunetin exhibited more-selective inhibition of PDE4 with IC(50) values of around 30 and 60 microM, respectively. Luteolin-7-glucoside exhibited dual inhibition of PDE2/PDE4 with an IC(50) value of around 40 microM. Diosmetin more-selectively inhibited PDE2 (IC(50) of 4.8 microM) than PDE1, PDE4, or PDE5. However, biochanin A more-selectively inhibited PDE4 (IC(50) of 8.5 microM) than PDE1 or PDE2. Apigenin inhibited PDE1-3 with IC(50) values of around 10-25 microM. Myricetin inhibited PDE1-4 with IC(50) values of around 10-40 microM. The same was true for quercetin, but we rather consider that it more-selectively inhibited PDE3 and PDE4 (IC(50) of < 10 microM). In conclusion, it is possible to synthesize useful drugs through elucidating the structure-activity relationships of flavonoids with respect to inhibition of PDE isozymes at concentrations used in this in vitro study. PMID:15476679

Ko, Wun-Chang; Shih, Chwen-Ming; Lai, Ya-Hsin; Chen, Jun-Hao; Huang, Hui-Lin

2004-11-15

213

Synthesis and structure-activity relationships of cetiedil analogues as blockers of the Ca(2+)-activated K+ permeability of erythrocytes.  

PubMed

Cetiedil, [2-cyclohexyl-2-(3-thienyl)ethanoic acid 2-(hexahydro-1H-azepin-1-yl)ethyl ester], which blocks the intermediate calcium-activated potassium ion permeability (IK(Ca)) in red blood cells, was used as a lead for investigating structure-activity relationships with the aim of determining the pharmacophore and of synthesizing agents of greater potency. A series of compounds having structures related to cetiedil was made and tested on rabbit erythrocytes. Channel blocking activity within the series was found to correlate well with octanol-water partition coefficients but not with the specific chemical structure of the acid moiety. However, whereas log P for the compounds spans a range of values over 4 orders of magnitude, potency only increases by 2 orders. This suggests that hydrophobic interactions with an active site on the channel are probably not the main determinants of activity. It seems more likely that increased lipophilicity enhances access to the channel, probably from within the cell membrane. In keeping with this interpretation, cetiedil methoiodide was found to be inactive. Triphenylethanoic was found to be a more effective acid grouping than 2-cyclohexyl-2-(3-thienyl)ethanoic, and its 2-(hexahydro-1H-azepin-l-yl)ethyl ester (11) was approximately 3 times more potent than cetiedil. The 9-benzylfluoren-9-yl carboxylic acid ester (21) was found to be approximately 9 times more active than cetiedil, and replacing -CO(2)- in 21 by an ethynyl (-C identical to C-) linkage (compound 26, UCL 1608) increased potency by some 15-fold over that of cetiedil. PMID:11563923

Roxburgh, C J; Ganellin, C R; Athmani, S; Bisi, A; Quaglia, W; Benton, D C; Shiner, M A; Malik-Hall, M; Haylett, D G; Jenkinson, D H

2001-09-27

214

Some methods of obtaining quantitative structure-activity relationships for quantities of environmental interest  

SciTech Connect

Methods are described for obtaining quantitative structure-activity relationships (QSAR) for the estimation of quantities of environmental interest. Toxicities of alkylamines and of alkyl alkanoates are well correlated by the alkyl bioactivity branching equation (ABB). Narcotic activities of 1,1-disubstituted ethylenes are correlated by the intermolecular forces bioactivity (IMF) equation. When the data set has a limited number of substituents in equivalent positions the group number (GN) equation, derivable from the IMF equation, can be used for correlation. It has been successfully applied to aqueous solubilities, 1-octanol-water partition coefficients, and bioaccumulation factors and ecological magnifications for organochlorine compounds. A combination of the omega method for combining data sets for different organisms with the GN equation has been used to correlate toxicities of organochlorine insecticides in two species of fish. Toxicities of carbamates have been correlated by a combination of the zeta method and the IMFB equation. The ABB and the GN equations are particularly useful in that they generally do not require parameter tables, and that the parameters they use are error-free. The methods presented here, as shown by the examples given, should make it possible to establish a collection of QSAR for toxicities, bioaccumulation factors, aqueous solubilities, partition coefficients, and other properties of sets of compounds of environmental interest. 29 references.

Charton, M.

1985-09-01

215

Structure-activity relationship modeling for predicting interactions with pregnane X receptor by recursive partitioning.  

PubMed

Pregnane X receptor (PXR) is a ligand-activated nuclear factor that upregulates the expression of proteins involved in the detoxification and clearance of xenobiotics, primarily cytochrome P450 3A4 (CYP3A4). Structure-activity relationship (SAR) analysis of PXR agonists is useful for avoiding unwanted pharmacokinetics due to drug-drug interactions. To perform large-scale ligand-based SAR modeling, we systematically collected information on chemical-PXR interactions from the PubMed database by using the text mining system we developed, and merged it with screening data registered in the PubChem BioAssay database and other published data. Curation of the data resulted in 270 human PXR agonists and 248 non-agonists. After the entire data set was divided into training and testing data sets, the training data set comprising 415 data entries (217 positive and 198 negative instances) was analyzed by a recursive partitioning method. The classification tree optimized by a cross-validation pruning algorithm gave an accuracy of 79.0%, and, for the external testing data set, could correctly classify PXR agonists and non-agonists at an accuracy of 70.9%. Descriptors chosen as splitting rules in the classification tree were generally associated with electronic properties of molecules, suggesting they had an important role in the modes of interaction. PMID:22453080

Yoshida, Shuya; Yamashita, Fumiyoshi; Itoh, Takayuki; Hashida, Mitsuru

2012-03-27

216

Identification, Structure-Activity Relationships and Molecular Modeling of Potent Triamine and Piperazine Opioid Ligands  

PubMed Central

Opioid receptors are important targets for pain management. Here, we report the synthesis and biological evaluation of three positional scanning combinatorial libraries, consisting of linear triamines and piperazines. A highly potent (14 nM) and selective (IC50(?)/IC50(?) = 71; IC50(?)/IC50(?) = 714) triamine for the ?-opioid receptor was found. In addition, non-selective ?-? binders were obtained, with binding affinities of 54 nM and 22 nM for ?- and ?-opioid receptors, respectively. Structure-activity relationships of each subset are described. 3D molecular alignments based on shape similarity to internal and external query molecules were carried out. For the combinatorial chemistry dataset studied here a 1.3 similarity cut-off value was observed to be efficient in the ROCS-based alignment method. Interactions from the overlays analyzed in the binding sites of homology models of the receptors revealed specific substitution patterns for enhancing binding affinity in the piperazine series. Pharmacophore modeling of the compounds found from the three combinatorial libraries was also performed. The pharmacophore model indicated that the important feature for receptor binding activity with the ?-receptor was the presence of at least one hydrogen bond acceptor and one aromatic hydrophobic group. Whereas for the ?-receptor two binding modes emerged with one set of compounds employing the hydrogen bond acceptor and aromatic hydrophobic group, and a second set possibly via interactions with the receptor by hydrophobic and ionic salt-bridges.

Yongye, Austin B.; Appel, Jon R.; Giulianotti, Marc A.; Dooley, Colette T.; Medina-Franco, Jose L.; Nefzi, Adel; Houghten, Richard A.; Martinez-Mayorga, Karina

2009-01-01

217

Some methods of obtaining quantitative structure-activity relationships for quantities of environmental interest.  

PubMed Central

Methods are described for obtaining quantitative structure-activity relationships (QSAR) for the estimation of quantities of environmental interest. Toxicities of alkylamines and of alkyl alkanoates are well correlated by the alkyl bioactivity branching equation (ABB). Narcotic activities of 1,1-disubstituted ethylenes are correlated by the intermolecular forces bioactivity (IMF) equation. When the data set has a limited number of substituents in equivalent positions the group number (GN) equation, derivable from the IMF equation, can be used for correlation. It has been successfully applied to aqueous solubilities, 1-octanol-water partition coefficients, and bioaccumulation factors and ecological magnifications for organochlorine compounds. A combination of the omega method for combining data sets for different organisms with the GN equation has been used to correlate toxicities of organochlorine insecticides in two species of fish. Toxicities of carbamates have been correlated by a combination of the zeta method and the IMFB equation. The ABB and the GN equations are particularly useful in that they generally do not require parameter tables, and that the parameters they use are error-free. The methods presented here, as shown by the examples given, should make it possible to establish a collection of QSAR for toxicities, bioaccumulation factors, aqueous solubilities, partition coefficients, and other properties of sets of compounds of environmental interest.

Charton, M

1985-01-01

218

Structure-activity relationship of natural and synthetic coumarins inhibiting the multidrug transporter P-glycoprotein.  

PubMed

A set of 32 natural and synthetic coumarins were tested in order to evaluate their activity on human leukemic cells (K562/R7) overexpressing P-glycoprotein (P-gp). Their ability to reduce the P-gp-mediated drug efflux of daunorubicin out of cells was evaluated at 10 microM. Four natural compounds, previously isolated from Calophyllum dispar (Clusiaceae) and substituted by a common alpha-(hydroxyisopropyl)dihydrofuran moiety, exhibited a significant inhibitory effect on P-gp when compared to the positive control cyclosporin A. A 3D-quantitative structure-activity relationship (3D-QSAR) analysis of the coumarins was performed using the biological results obtained by comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) of P-gp. Results showed a favorable electrostatic and steric volume, like the alpha-(hydroxyisopropyl)dihydrofuran moiety, beside C(5)-C(6) or C(7)-C(8) positions. In addition, the analysis revealed an important hydrophobic, neutral charge group, like phenyl, in position C(4) on the coumarinic ring. PMID:16824763

Raad, Imad; Terreux, Raphael; Richomme, Pascal; Matera, Eva-Laure; Dumontet, Charles; Raynaud, Jean; Guilet, David

2006-07-07

219

Syntheses and Structure-Activity Relationships of Novel 3?-Difluoromethyl and 3?-Trifluoromethyl-Taxoids  

PubMed Central

A series of novel 3?-difluoromethyl-taxoids and 3?-trifluoromethyl-taxoids with modifications at the C2 and C10 positions were synthesized and evaluated for their in vitro cytotoxicities against human breast carcinoma (MCF7-S, MCF7-R, LCC6-WT, LCC6-MDR), non-small cell lung carcinoma (H460) and colon adenocarcinoma (HT-29) cell lines. These second-generation fluoro-taxoids exhibited several times to more than 20 times better potency than paclitaxel against drug-sensitive cancer cell lines, MCF7-S, LCC6-WT, H460, and HT-29. These fluoro-taxoids also possess two orders of magnitude higher potency than paclitaxel against drug-resistant cancer cell lines, MCF7-R and LCC6-MDR. Structure-activity relationship study shows the importance of the C10 modification for increasing the activity against multidrug-resistant cancer cell lines. Effects of the C2-benzoate modifications on the potency in the 3-difluoromethyl-taxoid series are very clear (i.e., F < MeO < Cl < N3), while those in the 3-trifluoromethyl-taxoid series are less obvious. Also, different trends in the sensitivity to the C2-substitution are observed between drug-sensitive cell lines and drug-resistant cancer cell lines that overexpress efflux pumps.

Kuznetsova, Larissa V.; Pepe, Antonella; Ungureanu, Ioana M.; Pera, Paula; Bernacki, Ralph J.; Ojima, Iwao

2009-01-01

220

Biological activity, design, synthesis and structure activity relationship of some novel derivatives of curcumin containing sulfonamides.  

PubMed

Five series of curcumin derivatives with sulfonamides 3a-3e, 4a-4e, 5a-5e, 6a-6e and 7a-7e have been synthesized and evaluated for in vitro antibacterial activity against selected medically important gram-(+) and gram-(-) bacterial species viz. Staphylococcus aureus, Bacillus cereus, Salmonella typhi, Pseudomonas aeruginosa and Escherichia coli, and antifungal activity against few pathogenic fungal species viz. Aspergillus niger, Aspergillus flavus, Trichoderma viride and Curvularia lunata. The cytotoxicity has been determined by measuring IC50 values against human cell lines HeLa, Hep G-2, QG-56 and HCT-116. Among the compounds screened, 3a-3e showed the most potent biological activity against tested bacteria and fungi. Compounds 3a-3e displayed higher cytotoxicity than curcumin. The curcumin derivatives were also evaluated for in vivo anti-inflammatory activity. In contrast, the compounds 6a-6e and 7a-7e showed dramatically decrease in biological activity. PMID:23685942

Lal, Jaggi; Gupta, Sushil K; Thavaselvam, D; Agarwal, Dau D

2013-03-22

221

Antinociceptive activity and preliminary structure-activity relationship of chalcone-like compounds.  

PubMed

Chalcones belong to a class of alpha,beta,-unsaturated aromatic ketones which occur abundantly in nature, especially in plants. They are promising and interesting compounds due to their vast applications in pharmaceuticals, agriculture and industry. Several studies have shown that these compounds exert important biological activities in different experimental models. The present work deals with the antinociceptive activity, evaluated against the writhing test, of three series of chalcone-like compounds obtained by the Claisen-Schmidt condensation, using different aldehydes and substituted acetophenones. The results reveal that the compounds synthesized show a significant antinociceptive effect compared with nonsteroidal drugs such as aspirin, paracetamol and diclofenac. They also show that the electronic demand of the substituents is the dominant factor of the biological activity. PMID:19227830

Corrêa, Rogério; Fenner, Bruna Proiss; Buzzi, Fátima de Campos; Cechinel Filho, Valdir; Nunes, Ricardo José

222

Structure-activity relationship studies of orally active antimalarial 3,5-substituted 2-aminopyridines.  

PubMed

In an effort to address potential cardiotoxicity liabilities identified with earlier frontrunner compounds, a number of new 3,5-diaryl-2-aminopyridine derivatives were synthesized. Several compounds exhibited potent antiplasmodial activity against both the multidrug resistant (K1) and sensitive (NF54) strains in the low nanomolar range. Some compounds displayed a significant reduction in potency in the hERG channel inhibition assay compared to previously reported frontrunner analogues. Several of these new analogues demonstrated promising in vivo efficacy in the Plasmodium berghei mouse model and will be further evaluated as potential clinical candidates. The SAR for in vitro antiplasmodial and hERG activity was delineated. PMID:23189922

González Cabrera, Diego; Douelle, Frederic; Younis, Yassir; Feng, Tzu-Shean; Le Manach, Claire; Nchinda, Aloysius T; Street, Leslie J; Scheurer, Christian; Kamber, Jolanda; White, Karen L; Montagnat, Oliver D; Ryan, Eileen; Katneni, Kasiram; Zabiulla, K Mohammed; Joseph, Jayan T; Bashyam, Sridevi; Waterson, David; Witty, Michael J; Charman, Susan A; Wittlin, Sergio; Chibale, Kelly

2012-12-14

223

Oxazolones: new tyrosinase inhibitors; synthesis and their structure-activity relationships.  

PubMed

The tyrosinase inhibitory potential of seventeen synthesized oxazolone derivatives has been evaluated and their structure-activity relationships developed in the present work. All the synthesized derivatives, 3-19, demonstrated excellent in vitro tyrosinase inhibitory properties having IC50 values in the range of 1.23+/-0.37-17.73+/-2.69 microM, whereas standard inhibitors l-mimosine and kojic acid have IC50 values 3.68+/-0.02 and 16.67+/-0.52 microM,, respectively. Compounds 4-8 having IC50 values 3.11+/-0.95, 3.51+/-0.25, 3.23+/-0.66, 1.23 +/- 0.37, and 2.15+/-0.75, respectively, were found to be very active members of the series, even better than both the standard inhibitors. However, compounds 3, 9-11, 13, 14, 16, 17, and 19 were found to be better than kojic acid but not l-mimosine. (2-Methyl-4-[E,2Z)-3-phenyl-2-propenyliden]-1,3-oxazol-5(4H)-one (7) bearing a cinnamyol residue at C-4 of oxazolone moiety and an IC50 = 1.23+/-0.37 microM was found to be the most active one among all tested compounds. These studies reveal that the substitution of functional group (s) at C-4 and C-2 positions plays a vital role in the activity of this series of compounds. It is concluded that compound 7 may act as a potential lead molecule to develop new drugs for the treatment of tyrosinase based disorders. PMID:16750372

Khan, Khalid Mohammed; Mughal, Uzma Rasool; Khan, Mahmud Tareq Hassan; Zia-Ullah; Perveen, Shahnaz; Choudhary, Muhammad Iqbal

2006-06-05

224

Structure-activity relationship of a guanine-free oligodeoxynucleotide as immunopotent inhibitor.  

PubMed

Excessive innate immune response could contribute to the pathogenesis of inflammatory and autoimmune diseases. It is required to develop agents to inhibit the overwhelming innate immune response. SAT05f, an inhibitory ODN with CCT repeat sequence found in human microsatellite DNA, has been demonstrated to down-regulate TLR7/9-mediated innate immune response, protect mice from D-GalN/CpG ODN induced lethal shock, and reduce anti-ssDNA antibody level in the lupus-prone mice induced by chronic graft versus host disease (cGVHD). In this article, to explore the structure-activity relationship of SAT05f, we designed and synthesized a series of ODNs based on the sequence of SAT05f by changing repeat number of the CCT unit, substituting CCT unit with AAG at 3' end or 5' end or in the middle and by forming hairpin at 5' or 3' end, and tested their inhibitory effect on the CpG ODN induced proliferation and TNF-? production in murine immune cells. The results indicated that 1) at least 8 CCT units were required for a CCT repeat ODN to display its inhibitory activity; 2) CCT unit at 3' end of SAT05f was necessary for its full inhibitory activity; and 3) 5' end of SAT05f could be modified to design a more potent SAT05f derived inhibitory ODN. The data provided here would be helpful for finding a potent inhibitory ODN as a candidate medicament for the treatment of diseases associated with over-activated innate immune response. PMID:22664144

Zhang, Yong-Sheng; Wu, Xiu-Li; Wang, Ying; Sun, Ran; Yu, Yong-Li; Wang, Li-Ying

2012-06-01

225

Structure–Activity Relationships for Antioxidant Activities of a Series of Flavonoids in a Liposomal System  

Microsoft Academic Search

Structurally diverse plant phenolics were examined for their abilities to inhibit lipid peroxidation induced either by Fe(II) and Fe(III) metal ions or by azo-derived peroxyl radicals in a liposomal membrane system. The antioxidant abilities of flavonoids were compared with those of coumarin and tert-butylhydroquinone (TBHQ). The antioxidant efficacies of these compounds were evaluated on the basis of their abilities to

Arti Arora; Muraleedharan G. Nair; Gale M. Strasburg

1998-01-01

226

N-1-tert-butyl-substituted quinolones: in vitro anti-Mycobacterium avium activities and structure-activity relationship studies.  

PubMed Central

We determined the MICs of 63 quinolones against 14 selected reference and clinical strains of the Mycobacterium avium-Mycobacterium intracellulare complex. Sixty-one of the compounds were selected from the quinolone library at Parke-Davis, Ann Arbor, Mich., including N-1-tert-butyl-substituted agents. T 3761 and tosufloxacin were also tested. The activities of all 63 compounds were compared with those of ciprofloxacin and sparfloxacin. The results showed 45 of the quinolones to be active against the M. avium-M. intracellulare complex, with MICs at which 50% of the strains were inhibited (MIC50s) of less than 32 micrograms/ml. Twenty-four of these quinolones had activities equivalent to or greater than that of ciprofloxacin, and nine of them had activities equivalent to or greater than that of sparfloxacin. The most active compounds were the N-1-tert-butyl-substituted quinolones, PD 161315 and PD 161314, with MIC50s of 0.25 microgram/ml and MIC90s of 1 microgram/ml; comparable values for ciprofloxacin were 2 and 4 micrograms/ml, respectively, while for sparfloxacin they were 1 and 2 micrograms/ml, respectively. The next most active compounds, with MIC50s of 0.5 microgram/ml and MIC90s of 1 microgram/ml, were the N-1-cyclopropyl-substituted quinolones, PD 138926 and PD 158804. These values show that the tert-butyl substituent is at least as good as cyclopropyl in rendering high levels of antimycobacterial activity. However, none of the quinolones showed activity against ciprofloxacin-resistant laboratory-derived M. avium-M. intracellulare complex strains. A MULTICASE program-based structure-activity relationship analysis of the inhibitory activities of these 63 quinolones and 109 quinolones previously studied against the most resistant clinical strain of M. avium was also performed and led to the identification of two major biophores and two biophobes.

Klopman, G; Fercu, D; Renau, T E; Jacobs, M R

1996-01-01

227

Large-scale isolation of flavonolignans from Silybum marianum extract affords new minor constituents and preliminary structure-activity relationships.  

PubMed

The gram-scale isolation of the major flavonolignan diastereoisomers from milk thistle ( Silybum marianum) extract provided an entree into the isolation of two related analogues that are present in extremely minute quantities. The isolation and structure elucidation of these two new compounds, which we have termed isosilybin C and isosilybin D due to their structural similarities to isosilybin A and isosilybin B, respectively, afforded a preliminary analysis of structure-activity relationships toward prostate cancer growth, survival, and apoptotic endpoints. PMID:19941262

Sy-Cordero, Arlene; Graf, Tyler N; Nakanishi, Yuka; Wani, Mansukh C; Agarwal, Rajesh; Kroll, David J; Oberlies, Nicholas H

2009-11-25

228

Computational investigation on the structure-activity relationship of the biradical mechanism for monoamine oxidase.  

PubMed

Although a considerable amount of mechanistic data has accumulated in literature, the detailed mechanism for amine oxidation by monoamine oxidase is still controversial. The single electron transfer mechanism (SET) has been widely discussed, but not completely understood yet. In the present study, the modified SET mechanism, proposed by Silverman et al., was explored by quantum chemical calculations. The ONIOM method was applied with UDFT/B3LYP/6-31 + G(d,p) for the higher layer and with UHF/6-31G(d) for the lower layer. Isoalloxazin heterocyclic ring and benzylamine were employed in the calculations to represent flavin and the substrate, respectively. The substituents CH(3), OH, OCH(3), H, F, Cl, Br, CF(3) and NO(2) were incorporated at the para position of benzylamine to explore structure-activity relationships. The structures of the reactant complex, transition state and product complex were fully optimized. Activation energies and rate constants of all the reactions were calculated. The results obtained from the linear regression analysis showed that electron-donating groups at the para position of benzylamine increase the reaction rate. A linear but inverse correlation between the log of the calculated rate constants (log k) and the electronic parameter of the substituent was observed (R = 0.93). In accordance with this result, a relatively weak inverse correlation between the calculated log k and the experimental log k was obtained (R = 0.78). The results are contrary to the previous kinetic experiments and the computational study on the effect of p-substituents in the flavin reduction of MAO A by p-substituted benzylamine analogs. Therefore, they present negative evidence for the modeled biradical mechanism. PMID:21476070

Erdem, Safiye S; Büyükmenek?e, Burcu

2011-04-08

229

A relational learning approach to Structure-Activity Relationships in drug design toxicity studies.  

PubMed

It has been recognized that the development of new therapeutic drugs is a complex and expensive process. A large number of factors affect the activity in vivo of putative candidate molecules and the propensity for causing adverse and toxic effects is recognized as one of the major hurdles behind the current "target-rich, lead-poor" scenario. Structure-Activity Relationship (SAR) studies, using relational Machine Learning (ML) algorithms, have already been shown to be very useful in the complex process of rational drug design. Despite the ML successes, human expertise is still of the utmost importance in the drug development process. An iterative process and tight integration between the models developed by ML algorithms and the know-how of medicinal chemistry experts would be a very useful symbiotic approach. In this paper we describe a software tool that achieves that goal--iLogCHEM. The tool allows the use of Relational Learners in the task of identifying molecules or molecular fragments with potential to produce toxic effects, and thus help in stream-lining drug design in silico. It also allows the expert to guide the search for useful molecules without the need to know the details of the algorithms used. The models produced by the algorithms may be visualized using a graphical interface, that is of common use amongst researchers in structural biology and medicinal chemistry. The graphical interface enables the expert to provide feedback to the learning system. The developed tool has also facilities to handle the similarity bias typical of large chemical databases. For that purpose the user can filter out similar compounds when assembling a data set. Additionally, we propose ways of providing background knowledge for Relational Learners using the results of Graph Mining algorithms. PMID:21926445

Camacho, Rui; Pereira, Max; Costa, Vítor Santos; Fonseca, Nuno A; Adriano, Carlos; Simões, Carlos J V; Brito, Rui M M

2011-09-16

230

Structure-activity relationship of flavonoids active against lard oil oxidation based on quantum chemical analysis.  

PubMed

In this study, the antioxidant activities of 15 flavonoids against lard oil oxidation were determined by using the Rancimat test. Quercetin, dihydromyricetin, luteolin and kaempferol showed the strongest antioxidant activity, with protection factor values (PF) of 11.50, 11.29, 4.24 and 2.49, respectively. The role of conjugated hydroxyl groups of the B and C ring is discussed. By using the following descriptors: DeltaH(f) (the difference in heat of formation between flavonoids and their free radicals resulted after hydrogen atom donation) and H(BC) (the number of conjugated hydroxyl groups of the B and C ring), the result obtained in the antioxidant Rancimat test could be successfully explained. PMID:19104485

Yang, Ji-Guo; Liu, Ben-Guo; Liang, Gui-Zhao; Ning, Zheng-Xiang

2008-12-23

231

Synthesis, biological activity and structure-activity relationship of endomorphin-1/substance P derivatives.  

PubMed

Endomorphins have been shown to produce potent analgesia in various rodent models of pain. However, their central administration led to the development of tolerance and physical dependence. Conjugation of C-terminal substance P (SP) fragments to opioids and opioid peptides was previously shown to produce hybrid peptides with strong analgesic activity, with low or no propensity to develop tolerance. In this study, four peptides (2-5) comprised of endomorphin-1 (1) and C-terminal fragments of SP (four or five amino acids, SP(8-11) (2) or SP(7-11) (4), respectively), with an overlapping Phe residue, were synthesized. To overcome low metabolic stability and poor membrane permeability of the peptide, the N-terminus of 2 and 4 was further modified with a C10-carbon lipoamino acid (C10LAA) achieving 3 and 5, respectively. LAA-modification of the hybrid peptides resulted in a significant increase in metabolic stability and membrane permeability compared to peptides 1, 2 and 4. Compound 5 showed potent ?-opioid receptor binding affinity (K(i?)=3.87 ± 0.51 nM) with dose-dependent agonist activity in the nanomolar range (IC(50)=45 ± 13 nM). In silico modeling was used to investigate the binding modes and affinities of compounds 1-5 in the active site of ?-opioid receptors. The docking scores were in agreement with the K(i?) values obtained in the receptor binding affinity studies. The more active LAA-modified hybrid peptide showed a lower total interaction energy and higher negative value of MolDock score. PMID:23022277

Varamini, Pegah; Hussein, Waleed M; Mansfeld, Friederike M; Toth, Istvan

2012-09-11

232

Ether lipid derivatives: Antineoplastic activity in vitro and the structure-activity relationship  

Microsoft Academic Search

The antineoplastic activity of two ether lipid derivatives, the alkyl-lysophospholipid derivative (ALP) ET-18-OCH3 and the ether-linked lipoidal amine CP-46,665 was tested in a human tumor clonogenic assay (HTCA) in vitro. CP-46,665 suppresed\\u000a the colony formation of various human tumors with a slight dose response relation after 1 hr incubation and with a clear optimum\\u000a (85% response rate) after continuous exposure

Wolfgang E. Berdela; Daniel D. Yon Hoffb; Clemens Ungerc; Hans D. Schicka; Ulrich Finka; Anneliese Reicherta; Hansjorg Eibld; Johann Rastettera

1986-01-01

233

Structure-Activity Relationship of Flavonoids on Their Anti- Escherichia coli Activity and Inhibition of DNA Gyrase.  

PubMed

Flavonoids are potential sources of natural preservatives. The inhibitory activities of three polymethoxylated flavones (PMFs), three flavones, and four flavonols against Escherichia coli were determined using the microbroth dilution method. Flavonoid inhibitory activities against DNA gyrase from E. coli were estimated by DNA supercoiling. Kaempferol exhibited the greatest antibacterial activity [minimal inhibitory concentration (MIC) = 25 ?g/mL], while nobiletin showed the lowest activity (MIC = 177 ?g/mL). A good correlation was found between the pIC50 values and the corresponding pMIC values for the purified DNA gyrase (r = 0.9582). The structure-activity relationship analysis suggests that, for a good inhibitory effect, the hydroxyl group substitution at C-5 in the A ring and C-4' in the B ring and the methoxyl group substitution at C-3 and C-8 in the A ring are essential. The presence of the hydroxyl group at C-6 in the A ring, C-3' and C-5' in the B ring, and C-3 in the C ring and the methoxyl group at C-3' in the B ring greatly reduced inhibition of bacteria. These findings provide a theoretical basis for the development of high-bioactive and low-toxicity natural preservatives. PMID:23926942

Wu, Ting; Zang, Xixi; He, Mengying; Pan, Siyi; Xu, Xiaoyun

2013-08-20

234

Evolution of the international workshops on quantitative structure-activity relationships (QSARs) in environmental toxicology.  

PubMed

This presentation will review the evolution of the workshops from a scientific and personal perspective. From their modest beginning in 1983, the workshops have developed into larger international meetings, regularly held every two years. Their initial focus on the aquatic sphere soon expanded to include properties and effects on atmospheric and terrestrial species, including man. Concurrent with this broadening of their scientific scope, the workshops have become an important forum for the early dissemination of all aspects of qualitative and quantitative structure-activity research in ecotoxicology and human health effects. Over the last few decades, the field of quantitative structure/activity relationships (QSARs) has quickly emerged as a major scientific method in understanding the properties and effects of chemicals on the environment and human health. From substances that only affect cell membranes to those that bind strongly to a specific enzyme, QSARs provides insight into the biological effects and chemical and physical properties of substances. QSARs are useful for delineating the quantitative changes in biological effects resulting from minor but systematic variations of the structure of a compound with a specific mode of action. In addition, more holistic approaches are being devised that result in our ability to predict the effects of structurally unrelated compounds with (potentially) different modes of action. Research in QSAR environmental toxicology has led to many improvements in the manufacturing, use, and disposal of chemicals. Furthermore, it has led to national policies and international agreements, from use restrictions or outright bans of compounds, such as polychlorinated biphenyls (PCBs), mirex, and highly chlorinated pesticides (e.g. DDT, dieldrin) for the protection of avian predators, to alternatives for ozone-depleting compounds, to better waste treatment systems, to more powerful and specific acting drugs. Most of the recent advances in drug development could not have been achieved without the use of QSARs in one form or another. The pace of such developments is rapid and QSARs are the keystone to that progress. These workshops have contributed to this progress and will continue to do so in the future. PMID:17365955

Kaiser, K L E

235

Quantitative structure-activity relationship models of clinical pharmacokinetics: clearance and volume of distribution.  

PubMed

Reliable prediction of two fundamental human pharmacokinetic (PK) parameters, systemic clearance (CL) and apparent volume of distribution (Vd), determine the size and frequency of drug dosing and are at the heart of drug discovery and development. Traditionally, estimated CL and Vd are derived from preclinical in vitro and in vivo absorption, distribution, metabolism, and excretion (ADME) measurements. In this paper, we report quantitative structure-activity relationship (QSAR) models for prediction of systemic CL and steady-state Vd (Vdss) from intravenous (iv) dosing in humans. These QSAR models avoid uncertainty associated with preclinical-to-clinical extrapolation and require two-dimensional structure drawing as the sole input. The clean, uniform training sets for these models were derived from the compilation published by Obach et al. (Drug Metab. Disp. 2008, 36, 1385-1405). Models for CL and Vdss were developed using both a support vector regression (SVR) method and a multiple linear regression (MLR) method. The SVR models employ a minimum of 2048-bit fingerprints developed in-house as structure quantifiers. The MLR models, on the other hand, are based on information-rich electro-topological states of two-atom fragments as descriptors and afford reverse QSAR (RQSAR) analysis to help model-guided, in silico modulation of structures for desired CL and Vdss. The capability of the models to predict iv CL and Vdss with acceptable accuracy was established by randomly splitting data into training and test sets. On average, for both CL and Vdss, 75% of test compounds were predicted within 2.5-fold of the value observed and 90% of test compounds were within 5.0-fold of the value observed. The performance of the final models developed from 525 compounds for CL and 569 compounds for Vdss was evaluated on an external set of 56 compounds. The predictions were either better or comparable to those predicted by other in silico models reported in the literature. To demonstrate the practical application of the RQSAR approach, the structure of vildagliptin, a high-CL and a high-Vdss compound, is modified based on the atomic contributions to its predicted CL and Vdss to propose compounds with lower CL and lower Vdss. PMID:23451981

Gombar, Vijay K; Hall, Stephen D

2013-03-15

236

COMPUTER-ASSISTED STRUCTURE ACTIVITY RELATIONSHIPS OF NITROGENOUS CYCLIC COMPOUNDS TESTED IN SALMONELLA ASSAYS FOR MUTAGENICITY  

EPA Science Inventory

Study of the relationship between mutagenicity and molecular structure for a data set of nitrogenous cyclic compounds is reported. A computerized SAR system (ADAPT) was utilized to classify a data set of 114 nitrogenous cyclic compounds with 19 molecular descriptors. All of the d...

237

Structure-activity relationships to estimate the effective Henry's law coefficients of organics of atmospheric interest  

NASA Astrophysics Data System (ADS)

The Henry's law coefficient is a key property needed to address the multiphase behaviour of organics in the atmosphere. Methods that can reliably predict the values for the vast number of organic compounds of atmospheric interest are therefore required. The effective Henry's law coefficient H* in air-water systems at 298 K was compiled from literature for 488 organic compounds bearing functional groups of atmospheric relevance. This data set was used to assess the reliability of the HENRYWIN bond contribution method and the SPARC approach for the determination of H*. Moreover, this data set was used to develop GROMHE, a new Structure Activity Relationship (SAR) based on a group contribution approach. These methods estimate logH* with a Root Mean Square Error (RMSE) of 0.38, 0.61, and 0.73 log unit for GROMHE, SPARC and HENRYWIN respectively. The results show that for all these methods the reliability of the estimates decreases with increasing solubility. The main differences among these methods lie in H* prediction for compounds with H* greater than 103 M atm-1. For these compounds, the predicted values of logH* using GROMHE are more accurate (RMSE=0.53) than the estimates from SPARC or HENRYWIN (RMSE=0.98 and 1.12).

Raventos-Duran, T.; Camredon, M.; Valorso, R.; Aumont, B.

2010-02-01

238

Structure-activity relationships to estimate the effective Henry's law constants of organics of atmospheric interest  

NASA Astrophysics Data System (ADS)

The Henry's law constant is a key property needed to address the multiphase behaviour of organics in the atmosphere. Methods that can reliably predict the values for the vast number of organic compounds of atmospheric interest are therefore required. The effective Henry's law constant H* in air-water systems at 298 K was compiled from literature for 488 organic compounds bearing functional groups of atmospheric relevance. This data set was used to assess the reliability of the HENRYWIN bond contribution method and the SPARC approach for the determination of H*. Moreover, this data set was used to develop GROMHE, a new Structure Activity Relationship (SAR) based on a group contribution approach. These methods estimate logH* with a Root Mean Square Error (RMSE) of 0.38, 0.61, and 0.73 log units for GROMHE, SPARC and HENRYWIN respectively. The results show that for all these methods the reliability of the estimates decreases with increasing solubility. The main differences among these methods lie in H* prediction for compounds with H* greater than 103 M atm-1. For these compounds, the predicted values of logH* using GROMHE are more accurate (RMSE = 0.53) than the estimates from SPARC or HENRYWIN.

Raventos-Duran, T.; Camredon, M.; Valorso, R.; Mouchel-Vallon, C.; Aumont, B.

2010-08-01

239

Utilization of quantitative structure-activity relationships (QSARs) in risk assessment: Alkylphenols  

SciTech Connect

Alkylphenols are a class of environmentally pervasive compounds, found both in natural (e.g., crude oils) and in anthropogenic (e.g., wood tar, coal gasification waste) materials. Despite the frequent environmental occurrence of these chemicals, there is a limited toxicity database on alkylphenols. The authors have therefore developed a 'toxicity equivalence approach' for alkylphenols which is based on their ability to inhibit, in a specific manner, the enzyme cyclooxygenase. Enzyme-inhibiting ability for individual alkylphenols can be estimated based on the quantitative structure-activity relationship developed by Dewhirst (1980) and is a function of the free hydroxyl group, electron-donating ring substituents, and hydrophobic aromatic ring substituents. The authors evaluated the toxicological significance of cyclooxygenase inhibition by comparison of the inhibitory capacity of alkylphenols with the inhibitory capacity of acetylsalicylic acid, or aspirin, a compound whose low-level effects are due to cyclooxygenase inhibition. Since nearly complete absorption for alkylphenols and aspirin is predicted, based on estimates of hydrophobicity and fraction of charged molecules at gastrointestinal pHs, risks from alkylphenols can be expressed directly in terms of 'milligram aspirin equivalence,' without correction for absorption differences. They recommend this method for assessing risks of mixtures of alkylphenols, especially for those compounds with no chronic toxicity data.38 references.

Beck, B.D.; Toole, A.P.; Callahan, B.G.; Siddhanti, S.K. (Gradient Corporation, Cambridge, MA (United States))

1991-12-01

240

Compound toxicity screening and structure-activity relationship modeling in Escherichia coli.  

PubMed

Synthetic biology and metabolic engineering are used to develop new strategies for producing valuable compounds ranging from therapeutics to biofuels in engineered microorganisms. When developing methods for high-titer production cells, toxicity is an important element to consider. Indeed the production rate can be limited due to toxic intermediates or accumulation of byproducts of the heterologous biosynthetic pathway of interest. Conversely, highly toxic molecules are desired when designing antimicrobials. Compound toxicity in bacteria plays a major role in metabolic engineering as well as in the development of new antibacterial agents. Here, we screened a diversified chemical library of 166 compounds for toxicity in Escherichia coli. The dataset was built using a clustering algorithm maximizing the chemical diversity in the library. The resulting assay data was used to develop a toxicity predictor that we used to assess the toxicity of metabolites throughout the metabolome. This new tool for predicting toxicity can thus be used for fine-tuning heterologous expression and can be integrated in a computational-framework for metabolic pathway design. Many structure-activity relationship tools have been developed for toxicology studies in eukaryotes [Valerio (2009), Toxicol Appl Pharmacol, 241(3): 356-370], however, to the best of our knowledge we present here the first E. coli toxicity prediction web server based on QSAR models (EcoliTox server: http://www.issb.genopole.fr/?faulon/EcoliTox.php). PMID:22038678

Planson, Anne-Gaëlle; Carbonell, Pablo; Paillard, Elodie; Pollet, Nicolas; Faulon, Jean-Loup

2011-11-09

241

CORAL: quantitative structure-activity relationship models for estimating toxicity of organic compounds in rats.  

PubMed

For six random splits, one-variable models of rat toxicity (minus decimal logarithm of the 50% lethal dose [pLD50], oral exposure) have been calculated with CORAL software (http://www.insilico.eu/coral/). The total number of considered compounds is 689. New additional global attributes of the simplified molecular input line entry system (SMILES) have been examined for improvement of the optimal SMILES-based descriptors. These global SMILES attributes are representing the presence of some chemical elements and different kinds of chemical bonds (double, triple, and stereochemical). The "classic" scheme of building up quantitative structure-property/activity relationships and the balance of correlations (BC) with the ideal slopes were compared. For all six random splits, best prediction takes place if the aforementioned BC along with the global SMILES attributes are included in the modeling process. The average statistical characteristics for the external test set are the following: n = 119 ± 6.4, R(2) = 0.7371 ± 0.013, and root mean square error = 0.360 ± 0.037. PMID:21656789

Toropova, A P; Toropov, A A; Benfenati, E; Gini, G; Leszczynska, D; Leszczynski, J

2011-06-08

242

Discovery and Structure Activity Relationship of Small Molecule Inhibitors of Toxic ?-Amyloid-42 Fibril Formation*  

PubMed Central

Increasing evidence implicates A? peptides self-assembly and fibril formation as crucial events in the pathogenesis of Alzheimer disease. Thus, inhibiting A? aggregation, among others, has emerged as a potential therapeutic intervention for this disorder. Herein, we employed 3-aminopyrazole as a key fragment in our design of non-dye compounds capable of interacting with A?42 via a donor-acceptor-donor hydrogen bond pattern complementary to that of the ?-sheet conformation of A?42. The initial design of the compounds was based on connecting two 3-aminopyrazole moieties via a linker to identify suitable scaffold molecules. Additional aryl substitutions on the two 3-aminopyrazole moieties were also explored to enhance ?-? stacking/hydrophobic interactions with amino acids of A?42. The efficacy of these compounds on inhibiting A? fibril formation and toxicity in vitro was assessed using a combination of biophysical techniques and viability assays. Using structure activity relationship data from the in vitro assays, we identified compounds capable of preventing pathological self-assembly of A?42 leading to decreased cell toxicity.

Kroth, Heiko; Ansaloni, Annalisa; Varisco, Yvan; Jan, Asad; Sreenivasachary, Nampally; Rezaei-Ghaleh, Nasrollah; Giriens, Valerie; Lohmann, Sophie; Lopez-Deber, Maria Pilar; Adolfsson, Oskar; Pihlgren, Maria; Paganetti, Paolo; Froestl, Wolfgang; Nagel-Steger, Luitgard; Willbold, Dieter; Schrader, Thomas; Zweckstetter, Markus; Pfeifer, Andrea; Lashuel, Hilal A.; Muhs, Andreas

2012-01-01

243

Automated information extraction and structure-activity relationship analysis of cytochrome P450 substrates.  

PubMed

Information on CYP-chemical interactions was comprehensively explored by a text-mining technique, to confirm our previous structure-activity relationship model for CYP substrates (Yamashita et al. J. Chem. Inf. Model. 2008, 48, 364-369). The text-mining technique is based on natural language processing and can extract chemical names and their interaction patterns according to sentence context. After chemicals were automatically extracted and classified into CYP substrates, inhibitors, and inducers, 709 substrates were retrieved from the PubChem database and categorized as 216, 145, 136, 217, 156, and 379 substrates for CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4, respectively. Although the previous classification model was developed using data from only 161 compounds, the model classified the substrates found by text-mining analysis with reasonable accuracy. This confirmed the validity of both the multi-objective classification model for CYP substrates and the text-mining procedure. PMID:21247177

Yamashita, Fumiyoshi; Feng, Chunlai; Yoshida, Shuya; Itoh, Takayuki; Hashida, Mitsuru

2011-01-19

244

Design, synthesis and structure-activity relationship of rhenium 2-arylbenzothiazoles as ?-amyloid plaque binding agents.  

PubMed

To continue our efforts toward the development of (99m)Tc PiB analogs, we have synthesized 24 neutral and lipophilic Re (as a surrogate of (99m)Tc) 2-arylbenzothiazoles, and explored their structure-activity relationship for binding to A?1-40 fibrils. These Re complexes were designed and synthesized via the integrated approach, so their (99m)Tc analogs would have a greater chance of crossing the blood-brain barrier. While the lipophilicities (logPC18=1.59-3.53) of these Re 2-arylbenzothiazoles were all within suitable range, their binding affinities (Ki=30-617nM) to A?1-40 fibrils varied widely depending on the selection and integration of the tetradentate chelator into the 2-phenylbenzothiazole pharmacophore. For potential clinical applications, further refinement to obtain Re 2-arylbenzothiazoles with better binding affinities (<10nM) will likely be needed. The integrated approach reported here to generate compact, neutral and lipophilic Re 2-arylbenzothiazoles could be applied to other potent pharmacophores as well to convert other current A? PET tracers to their (99m)Tc analogs for more widespread application via the use of SPECT scanners. PMID:23411076

Pan, Jinhe; Mason, Neale S; Debnath, Manik L; Mathis, Chester A; Klunk, William E; Lin, Kuo-Shyan

2013-01-24

245

Quantitative structure-activity relationship to predict acute fish toxicity of organic solvents.  

PubMed

REACH regulation requires ecotoxicological data to characterize industrial chemicals. To limit in vivo testing, Quantitative Structure-Activity Relationships (QSARs) are advocated to predict toxicity of a molecule. In this context, the topic of this work was to develop a reliable QSAR explaining the experimental acute toxicity of organic solvents for fish trophic level. Toxicity was expressed as log(LC50), the concentration in mmol.L(-1) producing the 50% death of fish. The 141 chemically heterogeneous solvents of the dataset were described by physico-chemical descriptors and quantum theoretical parameters calculated via Density Functional Theory. The best subsets of solvent descriptors for LC50 prediction were chosen both through the Kubinyi function associated with Enhanced Replacement Method and a stepwise forward multiple linear regressions. The 4-parameters selected in the model were the octanol-water partition coefficient, LUMO energy, dielectric constant and surface tension. The predictive power and robustness of the QSAR developed were assessed by internal and external validations. Several techniques for training sets selection were evaluated: a random selection, a LC50-based selection, a balanced selection in terms of toxic and non-toxic solvents, a solvent profile-based selection with a space filling technique and a D-optimality onions-based selection. A comparison with fish LC50 predicted by ECOSAR model validated for neutral organics confirmed the interest of the QSAR developed for the prediction of organic solvent aquatic toxicity regardless of the mechanism of toxic action involved. PMID:23866172

Levet, A; Bordes, C; Clément, Y; Mignon, P; Chermette, H; Marote, P; Cren-Olivé, C; Lantéri, P

2013-07-15

246

Quantitative structure-activity relationships for weak acid respiratory uncouplers to Vibrio fisheri  

SciTech Connect

Acute toxicity values of 16 organic compounds thought to elicit their response via the weak acid respiratory uncoupling mechanism of toxic action were secured from the literature. Regression analysis of toxicities revealed that a measured 5-min V. fisheri potency value can be used as a surrogate for the 30-min value. Regression analysis of toxicity versus hydrophobicity, measured as the 1-octanol/water partition coefficient (log K{sub ow}), was used to formulate a quantitative structure-activity relationship (QSAR). The equation log pT{sub 30}{sup {minus}1} = 0.489(log K{sub ow}) + 0.126 was found to be a highly predictive model. This V. fisheri QSAR is statistically similar to QSARs generated from weak acid uncoupler potency data for Pimephales promelas survivability and Tetrahymena pyriformis population growth impairment. This work, therefore, suggests that the weak acid respiratory uncoupling mechanism of toxic action is present in V. fisheri, and as such is not restricted to mitochondria-containing organisms.

Schultz, T.W. [Univ. of Tennessee, Knoxville, TN (United States). Coll. of Veterinary Medicine; Cronin, M.T.D. [Liverpool John Moores Univ. (United Kingdom). School of Pharmacy and Chemistry

1997-02-01

247

Structure-Activity Relationships of ?-Keto Oxazole Inhibitors of Fatty Acid Amide Hydrolase  

PubMed Central

A systematic study of the structure–activity relationships (SAR) of 2b (OL-135), a potent inhibitor of fatty acid amide hydrolase (FAAH), is detailed targeting the C2 acyl side chain. A series of aryl replacements or substituents for the terminal phenyl group provided effective inhibitors (e.g., 5c, aryl = 1-napthyl, Ki = 2.6 nM) with 5hh (aryl = 3-Cl-Ph, Ki = 900 pM) being 5-fold more potent than 2b. Conformationally-restricted C2 side chains were examined and many provided exceptionally potent inhibitors of which 11j (ethylbiphenyl side chain) was established to be a 750 pM inhibitor. A systematic series of heteroatoms (O, NMe, S), electron-withdrawing groups (SO, SO2), and amides positioned within and hydroxyl substitutions on the linking side chain were investigated which typically led to a loss in potency. The most tolerant positions provided effective inhibitors (12p, 6-position S, Ki = 3 nM or 13d, 2-position OH, Ki = 8 nM) comparable in potency to 2b. Proteomic-wide screening of selected inhibitors from the systematic series of >100 candidates prepared revealed that they are selective for FAAH over all other mammalian serine proteases.

Hardouin, Christophe; Kelso, Michael J.; Romero, F. Anthony; Rayl, Thomas J.; Leung, Donmienne; Hwang, Inkyu; Cravatt, Benjamin F.; Boger, Dale L.

2008-01-01

248

Quantitative structure-activity relationship studies for the prediction of antifungal activity of N-arylbenzenesulfonamides against Botrytis cinerea.  

PubMed

The Botrytis cinerea is one of the most interesting fungal pathogens. It can infect almost every plant and plant part and cause early latent infections which damage the fruit before ripening. The QSAR is an alternative method for the research of new and better fungicides against B. cinerea. This paper describes the results of applying a topological sub-structural molecular design (TOPS-MODE) approach for predicting the antifungal activity of 28 N-arylbenzenesulfonamides. The model described 86.1% of the experimental variance, with a standard deviation of 0.223. Leave-one-out and leave-group-out cross validation was carried out with the aim of evaluating the predictive power of the model. The values of their respective squared correlations coefficients were 0.754 and 0.741. The TOPS-MODE approach was compared with three other predictive models, but none of these could explain more than 72.8% of the variance with the same number of variables. In addition, this approach enabled the assessment of the contribution of different bonds to antifungal activity, thereby making the relationships between structure and biological activity more transparent. It was found that the fungicidal activity of the chemicals analyzed was increased by the presence of a sulfonamide group bonded to two aromatics rings, making this group the most important of the molecule. The majority of the substituents present in the aromatic rings have an electron withdrawing effect and they contribute to a smaller degree than the sulfonamide group to the property under study. The aromatic moiety plays an important role in this activity; its contribution changes with different substituents. Generally, the nitro group has a positive and great contribution to the biological property but when this group is involved in some compounds in ortho effect with the SO2 moiety of the sulfonamide group a lower value of contribution is observed for both groups. PMID:16782373

Saíz-Urra, Liane; González, Maykel Pérez; Collado, Isidro G; Hernández-Galán, Rosario

2006-05-12

249

Structure Activity Relationships of ?-L-LNA Modified Phosphorothioate Gapmer Antisense Oligonucleotides in Animals  

PubMed Central

We report the structure activity relationships of short 14-mer phosphorothioate gapmer antisense oligonucleotides (ASOs) modified with ?-L-locked nucleic acid (LNA) and related modifications targeting phosphatase and tensin homologue (PTEN) messenger RNA in mice. ?-L-LNA represents the ?-anomer of enantio-LNA and modified oligonucleotides show LNA like binding affinity for complementary RNA. In contrast to sequence matched LNA gapmer ASOs which showed elevations in plasma alanine aminotransferase (ALT) levels indicative of hepatotoxicity, gapmer ASOs modified with ?-L-LNA and related analogs in the flanks showed potent downregulation of PTEN messenger RNA in liver tissue without producing elevations in plasma ALT levels. However, the ?-L-LNA ASO showed a moderate dose-dependent increase in liver and spleen weights suggesting a higher propensity for immune stimulation. Interestingly, replacing ?-L-LNA nucleotides in the 3?- and 5?-flanks with R-5?-Me-?-L-LNA but not R-6?-Me- or 3?-Me-?-L-LNA nucleotides, reversed the drug induced increase in organ weights. Examination of structural models of dinucleotide units suggested that the 5?-Me group increases steric bulk in close proximity to the phosphorothioate backbone or produces subtle changes in the backbone conformation which could interfere with recognition of the ASO by putative immune receptors. Our data suggests that introducing steric bulk at the 5?-position of the sugar-phosphate backbone could be a general strategy to mitigate the immunostimulatory profile of oligonucleotide drugs. In a clinical setting, proinflammatory effects manifest themselves as injection site reactions and flu-like symptoms. Thus, a mitigation of these effects could increase patient comfort and compliance when treated with ASOs.

Seth, Punit P; Jazayeri, Ali; Yu, Jeff; Allerson, Charles R; Bhat, Balkrishen; Swayze, Eric E

2012-01-01

250

Quantitative Structure Activity Relationship for Inhibition of Human Organic Cation/Carnitine Transporter (OCTN2)  

PubMed Central

Organic cation/carnitine transporter (OCTN2; SLC22A5) is an important transporter for L-carnitine homeostasis, but can be inhibited by drugs, which may cause L-carnitine deficiency and possibly other OCTN2-mediated drug-drug interactions. One objective was to develop a quantitative structure–activity relationship (QSAR) of OCTN2 inhibitors, in order to predict and identify other potential OCTN2 inhibitors and infer potential clinical interactions. A second objective was to assess two high renal clearance drugs that interact with OCTN2 in vitro (cetirizine and cephaloridine) for possible OCTN2-mediated drug-drug interactions. Using previously generated in vitro data of 22 drugs, a 3D quantitative pharmacophore model and a Bayesian machine learning model were developed. The four pharmacophore features include two hydrophobic groups, one hydrogen-bond acceptor, and one positive ionizable center. The Bayesian machine learning model was developed using simple interpretable descriptors and function class fingerprints of maximum diameter 6 (FCFP_6). An external test set of 27 molecules, including 15 newly identified OCTN2 inhibitors, and a literature test set of 22 molecules were used to validate both models. The computational models afforded good capability to identify structurally diverse OCTN2 inhibitors, providing a valuable tool to predict new inhibitors efficiently. Inhibition results confirmed our previously observed association between rhabdomyolysis and Cmax/Ki ratio. The two high renal clearance drugs cetirizine and cephaloridine were found not to be OCTN2 substrates and their diminished elimination by other drugs is concluded not to be mediated by OCTN2.

Diao, Lei; Ekins, Sean; Polli, James E.

2010-01-01

251

Structure-activity relationships of arodyn, a novel acetylated kappa opioid receptor antagonist.  

PubMed

We previously reported that the novel dynorphin A (Dyn A, Tyr-Gly-Gly-Phe-Leu-Arg-Arg-Ile-Arg-Pro-Lys-Leu-Lys-Trp-Asp-Asn-Gln) analog arodyn (Ac[Phe(1,2,3),Arg(4),d-Ala(8)]Dyn A-(1-11)NH(2), Bennett, M.A., Murray, T.F. & Aldrich, J.V. (2002) J. Med. Chem. vol. 45, pp. 5617-5619) is a kappa opioid receptor-selective peptide [K(i)(kappa) = 10 nm, K(i) ratio (kappa/mu/delta) = 1/174/583] which exhibits antagonist activity at kappa opioid receptors. In this study, a series of arodyn analogs was prepared and evaluated to explore the structure-activity relationships (SAR) of this peptide; this included an alanine scan of the entire arodyn sequence, sequential isomeric d-amino acid substitution in the N-terminal 'message' sequence, NMePhe substitution individually in positions 1-3, and modifications in position 1. The results for the Ala-substituted derivatives indicated that Arg(6) and Arg(7) are the most important residues for arodyn's nanomolar binding affinity for kappa opioid receptors. Ala substitution of the other basic residues (Arg(4), Arg(9) and Lys(11)) resulted in lower decreases in affinity for kappa opioid receptors (three- to fivefold compared with arodyn). Of particular interest, while [Ala(10)]arodyn exhibits similar kappa opioid receptor binding as arodyn, it displays higher kappa vs. mu opioid receptor selectivity [K(i) ratio (kappa/mu) = 1/350] than arodyn because of a twofold loss in affinity at mu opioid receptors. Surprisingly, the Tyr(1) analog exhibits a sevenfold decrease in kappa opioid receptor affinity, indicating that arodyn displays significantly different SAR than Dyn A; [Tyr(1)]arodyn also unexpectedly exhibits inverse agonist activity in the adenylyl cyclase assay using Chinese hamster ovary cells stably expressing kappa opioid receptors. Substitution of NMePhe in position 1 gave [NMePhe(1)]arodyn which exhibits high affinity [K(i)(kappa) = 4.56 nm] and exceptional selectivity for kappa opioid receptors [K(i) ratio (kappa/mu/delta) = 1/1100/>2170]. This peptide exhibits antagonistic activity in the adenylyl cyclase assay, reversing the agonism of 10 nm Dyn A-(1-13)NH(2). Thus [NMePhe(1)]arodyn is a highly kappa opioid receptor-selective antagonist that could be a useful pharmacological tool to study kappa opioid receptor-mediated activities. PMID:15787962

Bennett, M A; Murray, T F; Aldrich, J V

2005-03-01

252

Ranking of hair dye substances according to predicted sensitization potency: quantitative structure-activity relationships.  

PubMed

Allergic contact dermatitis following the use of hair dyes is well known. Many chemicals are used in hair dyes and it is unlikely that all cases of hair dye allergy can be diagnosed by means of patch testing with p-phenylenediamine (PPD). The objectives of this study are to identify all hair dye substances registered in Europe and to provide their tonnage data. The sensitization potential of each substance was then estimated by using a quantitative structure-activity relationship (QSAR) model and the substances were ranked according to their predicted potency. A cluster analysis was performed in order to help select a number of chemically diverse hair dye substances that could be used in subsequent clinical work. Various information sources, including the Inventory of Cosmetics Ingredients, new regulations on cosmetics, data on total use and ChemId (the Chemical Search Input website provided by the National Library of Medicine), were used in order to identify the names and structures of the hair dyes. A QSAR model, developed with the help of experimental local lymph node assay data and topological sub-structural molecular descriptors (TOPS-MODE), was used in order to predict the likely sensitization potential. Predictions for sensitization potential were made for the 229 substances that could be identified by means of a chemical structure, the majority of these hair dyes (75%) being predicted to be strong/moderate sensitizers. Only 22% were predicted to be weak sensitizers and 3% were predicted to be extremely weak or non-sensitizing. Eight of the most widely used hair dye substances were predicted to be strong/moderate sensitizers, including PPD - which is the most commonly used hair dye allergy marker in patch testing. A cluster analysis by using TOPS-MODE descriptors as inputs helped us group the hair dye substances according to their chemical similarity. This would facilitate the selection of potential substances for clinical patch testing. A patch-test series with potent, frequently used, substances representing various chemical clusters is suggested. This may prove useful in diagnosing PPD-negative patients with symptoms of hair dye allergy and would provide some clinical validation of the QSAR predictions. PMID:15606648

Søsted, H; Basketter, D A; Estrada, E; Johansen, J D; Patlewicz, G Y

253

Structure-function relationships affecting the insecticidal and miticidal activity of sugar esters.  

PubMed

Synthetic sugar esters are a relatively new class of insecticidal compounds that are produced by reacting sugars with fatty acids. The objective of this research was to determine how systematic alterations in sugar or fatty acid components of sugar ester compounds influenced their insecticidal properties. Sucrose octanoate, sorbitol octanoate, sorbitol decanoate, sorbitol caproate, xylitol octanoate, xylitol decanoate and xylitol dodecanoate were synthesized and evaluated against a range of arthropod pests. Dosage-mortality studies were conducted on pear psylla (Cacopsylla pyricola Foerster) on pear, tobacco aphid (Myzus nicotianae) Blackman and tobacco hornworm (Manduca sexta [Johannson]) on tobacco, and twospotted spider mite (Tetranychus urticae Koch) on apple in laboratory bioassays. These sugar esters were compared with insecticidal soap (M-Pede, Dow AgroSciences L.L.C., San Diego, CA), to determine how toxicologically similar these materials were against the arthropod pests. Substitutions in either the sugar or fatty acid component led to significant changes in the physical properties and insecticidal activity of these compounds. The sugar esters varied in their solubility in water and in emulsion stability, yet, droplet spread upon pear leaves occurred at low concentrations of 80-160 ppm and was strongly correlated with psylla mortalities (R2 = 0.73). Sequentially altering the sugar or fatty acid components from lower to higher numbers of carbon chains, or whether the sugar was a monosaccharide or disaccharide did not follow a predictable relationship to insecticidal activity. Intuitively, changing the hydrophile from sorbitol (C6) to xylitol (C5) would require a decrease in lipophile chain length to maintain hydrophilic-lipophilic balance (HLB) relationships, yet an increase in lipophile chain length was unexpectedly needed for increasing insecticidal activity. Thus, the HLB of these materials did not correlate with pear psylla mortalities. Initial insect bioassays and dosage-mortality data found significant differences among sugar ester compounds' toxicity to the range of arthropod species. Sucrose octanoate high in monoester content had the highest activity against the range of arthropod pests at low concentrations of 1200-2400 ppm. No single chemical structure for the xylitol or sorbitol esters were optimally effective against the range of arthropods we tested and sorbitol octanoate and xylitol decanoate had the highest insecticidal activity of this group. All of the sugar ester materials produced high T. urticae mortalities on apple at very low concentrations of 400 ppm. Overall, most of the sugar esters that were examined had superior insecticidal activity compared with insecticidal soap. Sugar ester chemistry offers a unique opportunity to design an insecticide or miticide specific to certain arthropod pests which would be valuable in crop integrated pest management (IPM) programs. Sucrose esters are currently used as additives in the food industry which makes them especially attractive as safe and effective insecticides. PMID:12852599

Puterka, Gary J; Farone, William; Palmer, Tracy; Barrington, Anthony

2003-06-01

254

Development of ribonucleotide reductase inhibitors: a review on structure activity relationships.  

PubMed

Ribonucleotide reductase (RNR, E.C. 1.17.4.1), which is composed of two dissimilar proteins (subunits), often referred as R1 (containing polythiols) and R2 (containing non-heme iron and a free tyrosyl radical), which contribute to the role played by the enzyme. RNRs are one of the important targets in anticancer and antiviral drug development and many RNR inhibitors have been discovered at the end of the 20(th) century; many of them are already in clinical use. Triapine (3-AP) is one of the important RNR inhibitors belonging to the class of thiosemicarbazone derivatives, used in the treatment of various cancers. The structure activity relationship (SAR) studies on the investigated RNR inhibitors showed that the nitrogen atom in the pyridine (or other heterocycles) forms coordination complexes with the metal ions along with the imine, oxo and thio atoms of the thiosemicarbazone or semicarbazone pharmacophores. The computational analyses results in the adenine and purine derivatives suggest that the nitrogen atoms in the adenine rings make several hydrogen bonds with the water molecules present in the active site, as well as Gly249 and Glu288 residues. The OH group in third position of the sugar moiety interacts with the Ser217 (C=O) and the water molecules through hydrogen bonds. The aromatic rings in the molecules interact with the tyrosine residues. The thiosemicarbazone or semicarbazone derivatives explain that the flexibility and polar properties in the thiosemicarbazone or semicarbazone pharmacophoric regions allow the molecules to coordinate with the metal ion (especially iron) present in the RNR enzymes. This review concluded that RNR inhibitors composed of different fragments such as aryl, heteroaryl, sugar moiety, polar groups, flexible bonds, etc which are required for the binding of the molecules to the RNR enzymes. Further, the fragmental analysis of the RNR inhibitors on different toxicological and metabolic targets can provide significant novel molecules with acceptable pharmacokinetic properties. PMID:24032510

Moorthy, Narayana S H N; Cerqueira, Nuno M F S A; Ramos, Maria J; Fernandes, Pedro A

2013-11-01

255

Does electron-correlation has any role in the quantitative structure-activity relationships?  

PubMed

For developing quantitative structure-activity relationships (QSARs), quantum-mechanical molecular descriptors based on the state-of-the-art quantum-mechanical methods such as Hartree-Fock (HF) method and density-functional theory (DFT), are now routinely employed. The validity of these quantum-mechanical methods, however, rests on the accurate estimation of electron-correlation energy. This work analyses the role of electron-correlation, using correlation energy as a molecular descriptor, in the QSARs. In particular, QSAR models, for the mutagenic activity of a set of nitrated polycyclic aromatic hydrocarbons (nitro-PAHs), are examined for the role of electron-correlation through state-of-the-art external validation parameters such as concordance correlation coefficient and recently proposed predictive squared correlation coefficients, namely, QF1(2), QF2(2), and QF3(2) etc. The electron-correlation contribution to the highest occupied and lowest unoccupied molecular orbital (HOMO/LUMO) energies is also analyzed. QSAR models based on the semi-empirical quantum-mechanical methods like PM6 and RM1 are also compared. It is found that the models, developed using electron-correlation contribution of the quantum-mechanical descriptors, are not only robust but also relatively more predictive than those developed with the HF and DFT descriptors. The latter are found to be even less reliable than PM6 and RM1 descriptors based models, which show comparable robustness and predictivity with those developed using electron correlation based descriptors. The external predictivity of model based on semi-empirical descriptors can be improved if electron-correlation contribution of the quantum-mechanical descriptors is explicitly included in the model. This work reports the first-ever use of electron-correlation energy and its contribution to the HOMO/LUMO energies as molecular descriptors. PMID:23501159

Vikas; Reenu; Chayawan

2013-02-20

256

Data Mining and Machine Learning Techniques for the Identification of Mutagenicity Inducing Substructures and Structure Activity Relationships of Noncongeneric Compounds  

Microsoft Academic Search

This paper explores the utility of data mining and machine learning algorithms for the induction of mutagenicity structure-activity relationships (SARs) from noncongeneric data sets. We compare (i) a newly developed algorithm (MOLFEA) for the generation of descriptors (molecular fragments) for noncongeneric compounds with traditional SAR approaches (molecular properties) and (ii) different machine learning algorithms for the induction of SARs from

Christoph Helma; Tobias Cramer; Stefan Kramer; Luc De Raedt

2004-01-01

257

The new chemicals process at the Environmental Protection Agency (EPA): structure-activity relationships for hazard identification and risk assessment  

Microsoft Academic Search

Section 5 of the Toxic Substances Control Act (TSCA) does not require any toxicity testing as a prerequisite for submission of a Premanufacturing Notice (PMN) for a new chemical. In order to compensate for the lack of actual test data, a process involving structure-activity relationships (SAR) for assessing hazard potential was constructed. The hazard assessment is then coupled with an

P. M. Wagner; J. V. Nabholz; R. J. Kent

1995-01-01

258

The relationship between molecular structure and biological activity of alkali metal salts of vanillic acid: Spectroscopic, theoretical and microbiological studies  

NASA Astrophysics Data System (ADS)

In this paper we investigate the relationship between molecular structure of alkali metal vanillate molecules and their antimicrobial activity. To this end FT-IR, FT-Raman, UV absorption and 1H, 13C NMR spectra for lithium, sodium, potassium, rubidium and caesium vanillates in solid state were registered, assigned and analyzed. Microbial activity of studied compounds was tested against Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, Proteus vulgaris, Bacillus subtilis and Candida albicans. In order to evaluate the dependence between chemical structure and biological activity of alkali metal vanillates the statistical analysis was performed for selected wavenumbers from FT-IR spectra and parameters describing microbial activity of vanillates. The geometrical structures of the compounds studied were optimized and the structural characteristics were determined by density functional theory (DFT) using at B3LYP method with 6-311++G** as basis set. The obtained statistical equations show the existence of correlation between molecular structure of vanillates and their biological properties.

?wis?ocka, Renata; Piekut, Jolanta; Lewandowski, W?odzimierz

259

Structure–activity relationships of tyrosinase inhibitory combinatorial library of 2,5-disubstituted-1,3,4-oxadiazole analogues  

Microsoft Academic Search

Here the tyrosinase inhibition studies of library of 2,5-disubstituted-1,3,4-oxadiazoles have been reported and their structure–activity relationship (SAR) also have been discussed. The library of the oxadiazoles was synthesized under the microwave irradiation and was structures of these were characterized by different spectral techniques. From this study it could be concluded that for a better inhibition of tyrosinase, electronegative substitution is

Mahmud Tareq Hassan Khan; Muhammad Iqbal Choudhary; Khalid Mohammed Khan; Mubeen Rani; Atta-ur-Rahman

2005-01-01

260

Tumor speciWc cytotoxicity of -glucosylceramide: structure-cytotoxicity relationship and anti-tumor activity in vivo  

Microsoft Academic Search

This study describes the structure-cytotoxicity relationship of -glucosylceramide (-GluCer) and its anti- tumor activity in vivo. Unglycosylated ceramide had no selective cytotoxicity which demonstrated that the sugar moiety plays a critical role for the expression of selective cytotoxicity by -GluCer. -Galactosylceramide also showed tumor speciWc cytotoxicity suggesting that the chemical structure of sugar group is not a factor for the

Hirosuke Oku; Changchun Li; Masayuki Shimatani; Hironori Iwasaki; Takayoshi Toda; Takafumi Okabe; Hisami Watanabe

2009-01-01

261

Synthesis, Biological Evaluation and Structure-Activity Relationships of Dithiolethiones as Inducers of Cytoprotective Phase 2 Enzymes  

PubMed Central

Dithiolethiones are a family of promising cancer chemopreventive agents, and induction of Phase 2 enzymes is key to their chemopreventive activities. Two dithiolethiones have been evaluated in humans for cancer prevention. While some chemopreventive activities were detected in several human studies, potential side effects are a concern. Herein, we report structure-activity relationships of 25 dithiolethiones. Several compounds show exceedingly potent and bladder specific activity in Phase 2 enzyme induction. Structural features responsible for such activity, as well as those inhibiting the activity, are discussed. Moreover, the compounds activate and depend on Nrf2 for their inductive activities. Nrf2 is a major transcriptional stimulator of cytoprotective genes and is critical for cancer prevention. Thus, several new dithiolethiones that are highly promising for bladder cancer prevention have been identified. Because the compounds act specifically in the bladder, the likelihood of potential systemic toxicity may be low.

Munday, Rex; Zhang, Yuesheng; Paonessa, Joseph D.; Munday, Christine M.; Wilkins, Alistair L.; Babu, Jacob

2010-01-01

262

Synthesis and structure-activity relationship studies in peripheral benzodiazepine receptor ligands related to alpidem.  

PubMed

The exploration of the structure-affinity relationships concerning a new class of peripheral benzodiazepine receptor (PBR) ligands related to alpidem has been pursued in order to evaluate the consistency of the structure-affinity relationships among different classes (and subclasses) of PBR ligands. The target amide derivatives were prepared following a previously published procedure based on the condensation of pyrrolo[3,4-b]quinoline derivatives 11a,b with glyoxylic acid mono-hydrate and the subsequent amidation of the acids obtained via mixed anhydride. On the other hand, the preparation of compound 9g lacking the pharmacophoric (delta1) carbonyl group involved: (a) the double sequential attack of the dimethylmethyleneammonium salt obtained from bis(dimethylamino)methane and acetyl chloride to pyrrolo[3,4-b]quinoline derivative 11b, (b) the quaternization of the obtained allylamine derivative 13 with methyl iodide, and (c) the palladium-catalyzed allylation of N-methyl-p-anisidine by quaternary allylammonium cation 14. The structure-affinity relationship trends observed in this subclass of tricyclic alpidem-related PBR ligands find correlations in other classes (or subclasses) of PBR ligands. This result supports the initial pharmacophoric hypothesis and suggests a common mode of interaction at the PBR binding site. PMID:18294852

Cappelli, Andrea; Giuliani, Germano; Valenti, Salvatore; Anzini, Maurizio; Vomero, Salvatore; Giorgi, Gianluca; Sogliano, Cristiana; Maciocco, Elisabetta; Biggio, Giovanni; Concas, Alessandra

2007-06-27

263

Quantitative structure-activity relationships (QSARs) using the novel marine algal toxicity data of phenols.  

PubMed

The present study reports for the first time in its entirety the toxicity of 30 phenolic compounds to marine alga Dunaliella tertiolecta. Toxicity of polar narcotics and respiratory uncouplers was strongly correlated to hydrophobicity as described by the logarithm of the octanol/water partition coefficient (Log P). Compounds expected to act by more reactive mechanisms, particularly hydroquinones, were shown to have toxicity in excess of that predicted by Log P. A quality quantitative structure-activity relationship (QSAR) was obtained with Log P and a 2D autocorrelation descriptor weighted by atomic polarizability (MATS3p) only after the removal of hydroquinones from the data set. In an attempt to model the whole data set including hydroquinones, 3D descriptors were included in the modeling process and three quality QSARs were developed using multiple linear regression (MLR). One of the most significant results of the present study was the superior performance of the consensus MLR model, obtained by averaging the predictions from each individual linear model, which provided excellent prediction accuracy for the test set (Q(test)²=0.94). The four-parameter Counter Propagation Artificial Neural Network (CP ANN) model, which was constructed using four out of six descriptors that appeared in the linear models, also provided an excellent external predictivity (Q(test)²=0.93). The proposed algal QSARs were further tested in their predictivity using an external set comprising toxicity data of 44 chemicals on freshwater alga Pseudokirchneriella subcapitata. The two-parameter global model employing a 3D descriptor (Mor24m) and a charge-related descriptor (C(ortho)) not only had high external predictivity (Q(ext)²=0.74), but it also had excellent external data set coverage (%97). PMID:23085159

Ertürk, M Do?a; Saçan, Melek Türker; Novic, Marjana; Minovski, Nikola

2012-06-29

264

Hemoglobin binding of arylamines and nitroarenes: molecular dosimetry and quantitative structure-activity relationships.  

PubMed Central

N-Oxidation and nitroreduction to yield N-hydroxyarylamines are metabolic steps that are crucial for the genotoxic properties of aromatic amines and nitroarenes, respectively. N-Hydroxyarylamines can form adducts with DNA, tissue proteins, and the blood proteins albumin and hemoglobin in a dose-dependent manner. The determination of hemoglobin adducts is a useful tool for biomonitoring exposed populations. We have established the hemoglobin binding index (HBI) [(mmole compound/mole Hb)/(mmole compound/kg body weight)] of several aromatic amines and nitroarenes in female Wistar rats. Incorporating values obtained by other researchers in the same rat strain, the logarithm of hemoglobin binding (log HBI) was plotted against several physicochemical parameters and against calculated electronic descriptors of nitroarenes and arylamines. Most arylamines and nitroarenes form hydrolyzable (e.g., sulfinamide) adducts with hemoglobin in rats. The amount of hemoglobin binding decreases with the oxidizability of the arylamines, except for compounds that are substituted with halogens in ortho or meta position. For halogen-substituted arylamines, the amount of hemoglobin binding is directly proportional to the pKa. Hemoglobin binding of nitroarenes increases with the reducibility of the nitro group. The structure activity relationships (SAR) for hemoglobin binding of nitroarenes and arylamines are comparable. The SAR found for hemoglobin binding were compared with the SAR found in the literature for mutagenicity, carcinogenicity, and cytotoxicity of arylamines and nitroarenes. In general, the mutagenicity or carcinogenicity of arylamines increases with their oxidizability. This first set of data suggests that the levels of hemoglobin binding, mutagenicity, and carcinogenicity of arylamines are not determined by the same electronic properties of the compounds, or not by these properties alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Sabbioni, G

1994-01-01

265

Quantitative structure-activity relationships for organophosphates binding to trypsin and chymotrypsin.  

PubMed

Organophosphate (OP) nerve agents such as sarin, soman, tabun, and O-ethyl S-[2-(diisopropylamino) ethyl] methylphosphonothioate (VX) do not react solely with acetylcholinesterase (AChE). Evidence suggests that cholinergic-independent pathways over a wide range are also targeted, including serine proteases. These proteases comprise nearly one-third of all known proteases and play major roles in synaptic plasticity, learning, memory, neuroprotection, wound healing, cell signaling, inflammation, blood coagulation, and protein processing. Inhibition of these proteases by OP was found to exert a wide range of noncholinergic effects depending on the type of OP, the dose, and the duration of exposure. Consequently, in order to understand these differences, in silico biologically based dose-response and quantitative structure-activity relationship (QSAR) methodologies need to be integrated. Here, QSAR were used to predict OP bimolecular rate constants for trypsin and ?-chymotrypsin. A heuristic regression of over 500 topological/constitutional, geometric, thermodynamic, electrostatic, and quantum mechanical descriptors, using the software Ampac 8.0 and Codessa 2.51 (SemiChem, Inc., Shawnee, KS), was developed to obtain statistically verified equations for the models. General models, using all data subsets, resulted in R(2) values of .94 and .92 and leave-one-out Q(2) values of 0.9 and 0.87 for trypsin and ?-chymotrypsin. To validate the general model, training sets were split into independent subsets for test set evaluation. A y-randomization procedure, used to estimate chance correlation, was performed 10,000 times, resulting in mean R(2) values of .24 and .3 for trypsin and ?-chymotrypsin. The results show that these models are highly predictive and capable of delineating the complex mechanism of action between OP and serine proteases, and ultimately, by applying this approach to other OP enzyme reactions such as AChE, facilitate the development of biologically based dose-response models. PMID:21120745

Ruark, Christopher D; Hack, C Eric; Robinson, Peter J; Gearhart, Jeffery M

2011-01-01

266

Quantitative structure-activity relationships (QSARs) for the transformation of organic micropollutants during oxidative water treatment.  

PubMed

Various oxidants such as chlorine, chlorine dioxide, ferrate(VI), ozone, and hydroxyl radicals can be applied for eliminating organic micropollutant by oxidative transformation during water treatment in systems such as drinking water, wastewater, and water reuse. Over the last decades, many second-order rate constants (k) have been determined for the reaction of these oxidants with model compounds and micropollutants. Good correlations (quantitative structure-activity relationships or QSARs) are often found between the k-values for an oxidation reaction of closely related compounds (i.e. having a common organic functional group) and substituent descriptor variables such as Hammett or Taft sigma constants. In this study, we developed QSARs for the oxidation of organic and some inorganic compounds and organic micropollutants transformation during oxidative water treatment. A number of 18 QSARs were developed based on overall 412 k-values for the reaction of chlorine, chlorine dioxide, ferrate, and ozone with organic compounds containing electron-rich moieties such as phenols, anilines, olefins, and amines. On average, 303 out of 412 (74%) k-values were predicted by these QSARs within a factor of 1/3-3 compared to the measured values. For HO(·) reactions, some principles and estimation methods of k-values (e.g. the Group Contribution Method) are discussed. The developed QSARs and the Group Contribution Method could be used to predict the k-values for various emerging organic micropollutants. As a demonstration, 39 out of 45 (87%) predicted k-values were found within a factor 1/3-3 compared to the measured values for the selected emerging micropollutants. Finally, it is discussed how the uncertainty in the predicted k-values using the QSARs affects the accuracy of prediction for micropollutant elimination during oxidative water treatment. PMID:22939392

Lee, Yunho; von Gunten, Urs

2012-06-16

267

Three-dimensional quantitative structure–activity relationship (3D-QSAR) studies of tricyclic oxazolidinones as antibacterial agents  

Microsoft Academic Search

Oxazolidinones exemplified by eprezolid and linezolid are a new class of antibacterials that are active against Gram positive and anaerobic bacteria including methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant Staphylococcus epidermidis (MRSE) and vancomycin resistant enterococci (VRE). In an effort to have a better antibacterial agent in the oxazolidinone class, we have performed three-dimensional quantitative structure–activity relationship (3D-QSAR) studies for a series

Bulusu Gopalakrishnan; Akash Khandelwal; Shaikh Abdul Rajjak; Natesan Selvakumar; Jagattaran Das; Sanjay Trehan; Javed Iqbal; Magadi Sitaram Kumar

2003-01-01

268

Quantitative structure activities relationships of some 2-mercaptoimidazoles as CCR2 inhibitors using genetic algorithm-artificial neural networks.  

PubMed

Quantitative relationships between structures of twenty six of 2-mercaptoimidazoles as C-C chemokine receptor type 2 (CCR2) inhibitors were assessed. Modeling of the biological activities of compounds of interest as a function of molecular structures was established by means of genetic algorithm multivariate linear regression (GA-MLR) and genetic algorithm (GA-ANN). The results showed that, the pIC50 values calculated by GA-ANN are in good agreement with the experimental data, and the performance of the artificial neural networks regression model is superior to the multivariate linear regression-based (MLR) model. With respect to the obtained results, it can be deduced that there is a non-linear relationship between the pIC50 s and the calculated structural descriptors of the 2-mercaptoimidazoles. The obtained models were able to describe about 78% and 93% of the variance in the experimental activity of molecules in training set, respectively. The study provided a novel and effective approach for predicting biological activities of 2-mercaptoimidazole derivatives as CCR2 inhibitors and disclosed that combined genetic algorithm and GA-ANN can be used as a powerful chemometric tools for quantitative structure activity relationship (QSAR) studies. PMID:24019819

Saghaie, L; Shahlaei, M; Fassihi, A

2013-04-01

269

Oximes: Inhibitors of Human Recombinant Acetylcholinesterase. A Structure-Activity Relationship (SAR) Study.  

PubMed

Acetylcholinesterase (AChE) reactivators were developed for the treatment of organophosphate intoxication. Standard care involves the use of anticonvulsants (e.g., diazepam), parasympatolytics (e.g., atropine) and oximes that restore AChE activity. However, oximes also bind to the active site of AChE, simultaneously acting as reversible inhibitors. The goal of the present study is to determine how oxime structure influences the inhibition of human recombinant AChE (hrAChE). Therefore, 24 structurally different oximes were tested and the results compared to the previous eel AChE (EeAChE) experiments. Structural factors that were tested included the number of pyridinium rings, the length and structural features of the linker, and the number and position of the oxime group on the pyridinium ring. PMID:23959117

Sepsova, Vendula; Karasova, Jana Zdarova; Korabecny, Jan; Dolezal, Rafael; Zemek, Filip; Bennion, Brian J; Kuca, Kamil

2013-08-16

270

A Binding Site Model and Structure-Activity Relationships for the Rat A3 Adenosine Receptor  

PubMed Central

SUMMARY A novel adenosine receptor, the A3 receptor, has recently been cloned. We have systematically investigated the hitherto largely unexplored structure-activity relationships (SARs) for binding at A3 receptors, using 125I-N6-2-(4-aminophenyl)ethyladenosine as a radioligand and membranes from Chinese hamster ovary cells stably transfected with the rat A3-cDNA. As is the case for A1 and A2a, receptors, substitutions at the N6 and 5? positions of adenosine, the prototypic agonist ligand, may yield fairly potent compounds. However, the highest affinity and A3 selectivity is found for N6,5?-disubstituted compounds, in contrast to A1 and A2a receptors. Thus, N6-benzyladenosine-5?-N-ethylcarboxamide is highly potent (Ki, 6.8 nM) and moderately selective (13- and 14-fold versus A1 and A2a). The N6 region of the A3 receptor also appears to tolerate hydrophilic substitutions, in sharp contrast to the other subtypes. Potencies of N6,5?-disubstituted compounds in inhibition of adenylate cyclase via A3 receptors parallel their high affinity in the binding assay. None of the typical xanthine or nonxanthine (A1/A2) antagonists tested show any appreciable affinity for rat A3 receptors. 1,3-Dialkylxanthines did not antagonize the A3 agonist-induced inhibition of adenylate cyclase. A His residue in helix 6 that is absent in A3 receptors but present in A1/A2 receptors may be causal in this respect. In a molecular model for the rat A3 receptor, this mutation, together with an increased bulkiness of residues surrounding the ligand, make antagonist binding unfavorable when compared with a previously developed A1 receptor model. Second, this A3 receptor model predicted similarities with A1 and A2 receptors in the binding requirements for the ribose moiety and that xanthine-7-ribosides would bind to rat A3 receptors. This hypothesis was supported experimentally by the moderate affinity (Ki 6 ?M) of 7-riboside of 1,3-dibutylxanthine, which appears to be a partial agonist at rat A3 receptors. The model presented here, which is consistent with the detailed SAR found in this study, may serve to suggest future chemical modification, site-directed mutagenesis, and SAR studies to further define essential characteristics of the ligand-receptor interaction and to develop even more potent and selective A3 receptor ligands.

VAN GALEN, PHILIP J. M.; VAN BERGEN, ANDREW H.; GALLO-RODRIGUEZ, CAROLA; MELMAN, NELI; OLAH, MARK E.; IJZERMAN, AD P.; STILES, GARY L.; JACOBSON, KENNETH A.

2012-01-01

271

Design, Synthesis, and Structure-Activity Relationship of Substrate Competitive, Selective, and in Vivo Active Triazole and Thiadiazole inhibitors of the c-Jun N-Terminal Kinase  

PubMed Central

We report comprehensive structure activity relationship studies on a novel series of c-Jun N-terminal kinase (JNK) inhibitors. The compounds are substrate competitive inhibitors that bind to the docking site of the kinase. The reported medicinal chemistry and structure-based optimizations studies resulted in the discovery of selective and potent thiadiazole JNK inhibitors that displays promising in vivo activity in mouse models of insulin insensitivity.

De, Surya K.; Stebbins, John L.; Chen, Li-Hsing; Riel-Mehan, Megan; Machleidt, Thomas; Dahl, Russell; Yuan, Hongbin; Emdadi, Aras; Barile, Elisa; Chen, Vida; Murphy, Ria; Pellecchia, Maurizio

2009-01-01

272

Synthesis and structure-activity relationships of novel amino/nitro substituted 3-arylcoumarins as antibacterial agents.  

PubMed

A new series of amino/nitro-substituted 3-arylcoumarins were synthesized and their antibacterial activity against clinical isolates of Staphylococcus aureus (Gram-positive) and Escherichia coli (Gram-negative) was evaluated. Some of these molecules exhibited antibacterial activity against S. aureus comparable to the standards used (oxolinic acid and ampicillin). The preliminary structure-activity relationship (SAR) study showed that the antibacterial activity against S. aureus depends on the position of the 3-arylcoumarin substitution pattern. With the aim of finding the structural features for the antibacterial activity and selectivity, in the present manuscript different positions of nitro, methyl, methoxy, amino and bromo substituents on the 3-arylcoumarin scaffold were reported. PMID:23348993

Matos, Maria J; Vazquez-Rodriguez, Saleta; Santana, Lourdes; Uriarte, Eugenio; Fuentes-Edfuf, Cristina; Santos, Ysabel; Muñoz-Crego, Angeles

2013-01-24

273

Phosphodiesterase inhibitors. Part 1: Synthesis and structure–activity relationships of pyrazolopyridine–pyridazinone PDE inhibitors developed from ibudilast  

Microsoft Academic Search

Ibudilast [1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one] is a nonselective phosphodiesterase inhibitor used clinically to treat asthma. Efforts to selectively develop the PDE3- and PDE4-inhibitory activity of ibudilast led to replacement of the isopropyl ketone by a pyridazinone heterocycle. Structure–activity relationship exploration in the resulting 6-(pyrazolo[1,5-a]pyridin-3-yl)pyridazin-3(2H)-ones revealed that the pyridazinone lactam functionality is a critical determinant for PDE3-inhibitory activity, with the nitrogen preferably unsubstituted. PDE4

Robert W. Allcock; Haakon Blakli; Zhong Jiang; Karen A. Johnston; Keith M. Morgan; Georgina M. Rosair; Kazuhiko Iwase; Yasushi Kohno; David R. Adams

2011-01-01

274

Quantitative Structure–Activity Relationship and Quantitative Structure–Pharmacokinetics Relationship of 1,4-Dihydropyridines and Pyridines as Multidrug Resistance Modulators  

Microsoft Academic Search

Purpose. The aim of this study was to develop quantitative structureYactivity\\/pharmacokinetic relationships (QSAR\\/QSPKR) for a series of synthesized 1,4-dihydropyridines (DHPs) and pyridines as P-glycoprotein (P-gp) inhibitors. Methods. Molecular descriptors of test compounds were generated by 3D molecular modeling using SYBYL and KowWin programs. Forward inclusion coupled with multiple linear regression (MLR) was used to derive a QSAR equation for Ca

Xiao-Fei Zhou; Qingxiang Shao; Robert A. Coburn; Marilyn E. Morris

2005-01-01

275

Peptide scanning for studying structure-activity relationships in drug discovery.  

PubMed

Peptide-based therapeutics have grown in importance over the last few decades. Furthermore, peptides have been extensively used as lead compounds in the drug discovery process to investigate the nature of chemical space required for molecular recognition and activity at a variety of targets. This critical commentary reviews scanning techniques, which employ natural and non-proteinogenic amino acids to facilitate understanding of structural requirements for peptide biological activity. The value of sequence analysis by such methods is highlighted by examples, in which the elements for peptide affinity and activity have been elucidated and employed to prepare peptidomimetic leads for drug development. PMID:23253136

Jamieson, Andrew G; Boutard, Nicolas; Sabatino, David; Lubell, William D

2013-01-01

276

Exploring quantitative structure–activity relationship studies of antioxidant phenolic compounds obtained from traditional Chinese medicinal plants  

Microsoft Academic Search

In the present work, quantitative structure–activity relationship (QSAR) models have been built for a wide variety of antioxidant phenolic compounds obtained from traditional Chinese medicinal plants, with their Trolox equivalent antioxidant capacity measured using 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical and 2,2?-azinobis-(3-ethylbenzothiazoline-6-sulphonic acid) radical (ABTS) assay methods. Non-linear models obtained using genetic partial least-squares technique were acceptable both in terms of internal and

Indrani Mitra; Achintya Saha; Kunal Roy

2010-01-01

277

The Effect of Secoisolariciresinol on 3t3-L1 Adipocytes and the Relationship Between Molecular Structure and the Activity  

Microsoft Academic Search

\\u000a Secoisolariciresinol (SECO) is one of the lignans contained in flaxseed. SECO has some stereoisomeric forms, and they exist\\u000a as the racemic form in flaxseed. Therefore, we stereoselectively synthesized (+)-SECO, (–)-SECO, and meso-SECO forms. In this study, we focused on the effects of SECOs on the regulation of 3T3-L1 adipocytes, and revealed the structure-activity\\u000a relationships. As a result, (–)-SECO accelerated adiponectin

Shiori Tominaga; Takuya Sugahara; Sogo Nishimoto; Manami Yamawaki; Yuki Nakashima; Taro Kishida; Koichi Akiyama; Masafumi Maruyama; Satoshi Yamauchi

278

A structure-activity relationship study of flavonoids as inhibitors of E. coli by membrane interaction effect.  

PubMed

Flavonoids exhibit a broad range of biological activities including antibacterial activity. However, the mechanism of their antibacterial activity has not been fully investigated. The antibacterial activity and membrane interaction of 11 flavonoids (including 2 polymethoxyflavones and 4 isoflavonoids) against Escherichia coli were examined in this study. The antibacterial capacity was determined as flavonoids>polymethoxyflavones>isoflavonoids. Using fluorescence, it was observed that the 5 flavonoids rigidified the liposomal membrane, while the polymethoxyflavones and isoflavonoids increased membrane fluidity. There was a significant positive correlation between antibacterial capacity and membrane rigidification effect of the flavonoids. A quantitative structure-activity relationship (QSAR) study demonstrated that the activity of the flavonoid compounds can be related to molecular hydrophobicity (CLogP) and charges on C atom at position3 (C3). The QSAR model could be used to predict the antibacterial activity of flavonoids which could lead to natural compounds having important use in food and medical industry. PMID:23938956

Wu, Ting; He, Mengying; Zang, Xixi; Zhou, Ying; Qiu, Tianfu; Pan, Siyi; Xu, Xiaoyun

2013-08-09

279

Structure-Activity Relationship of a New Class of Anti-Hepatitis B Virus Agents  

PubMed Central

N-Nonyl-deoxy-galactonojirimycin (N-nonyl-DGJ) has been shown to reduce the amount of hepatitis B virus (HBV) produced by tissue cultures under conditions where cell viability is not affected. We show here that the compound N-nonyl-DGJ was effective against lamivudine-resistant HBV mutants bearing the YMDD motif in the polymerase gene, consistent with the compound's activity being distinct from those of nucleoside inhibitors. To better understand the chemical structures that influence its antiviral activity, a series of imino sugar derivatives were made and tested for their antiviral activity against HBV. This work suggests that the antiviral activity of the alkovirs requires an alkyl chain length of at least eight carbons but that the galactose-based head group can be modified with little or no loss in activity.

Mehta, Anand; Conyers, Bertha; Tyrrell, D. L. J.; Walters, Kathie-Anne; Tipples, Graham A.; Dwek, Raymond A.; Block, Timothy M.

2002-01-01

280

Structure-antioxidant activity relationships in a series of NO-donor phenols.  

PubMed

Recently we reported a new class of NO-donor phenols that could be of interest in the treatment of many forms of cardiovascular disease (CD). Their potencies as inhibitors of ferrous salt/ascorbate-induced peroxidation of membrane lipids of rat hepatocytes were assessed as pIC(50) values through the TBARS assay. In this work we aimed to find quantitative relationships between the antioxidant activity of these compounds and appropriate molecular descriptors. In particular, we determined their log P(oct), their reactivity (log Z) in reaction with the 2,2-diphenyl-1-picrylhydrazyl radical (DPPH(.)), and the theoretical parameter DeltaH(abs), which describes the enthalpy of homolytic O--H bond cleavage. The QSAR equations found through the classical Hansch approach allowed us to draw interesting conclusions on the possible mechanisms of reaction with radicals in the various environments, while underlining the role of lipophilicity in antioxidant activity. PMID:18626883

Tosco, Paolo; Marini, Elisabetta; Rolando, Barbara; Lazzarato, Loretta; Cena, Clara; Bertinaria, Massimo; Fruttero, Roberta; Reist, Marianne; Carrupt, Pierre-Alain; Gasco, Alberto

2008-09-01

281

Structure-activity relationships in platelet-activating factor (PAF). 8. Tetrahydrofuran derivatives as dual PAF antagonists and acetylcholinesterase inhibitors: anti-acetylcholinesterase activity and comparative SAR.  

PubMed

2,5-disubstituted tetrahydrofuran derivatives display a dual functionality: they are PAF antagonists and acetylcholinesterase (AChE) inhibitors. In vitro anti-AChE activity and in vivo trials are presented herein. These compounds are competitive and potent AChE inhibitors. Structure-activity relationships are described and compared with PAF-antagonist results. The presence of an onium group, a suitable distance supplied by a chain of 7 or 10 carbon atoms separating the function from the polar head and an appreciable chain hydrophobicity (4 < sigma f < 7) are the main features required for a dual activity. The derivatives are evaluated in a mouse passive avoidance model. Only compounds with both activities are able to reverse scopolamine-induced amnesia. In addition, they display a very weak toxicity. PMID:8816985

Le Texier, L; Favre, E; Ronzani, N; Massicot, F; Blavet, N; Pirotzky, E; Godfroid, J J

1996-05-01

282

Structural development of benzhydrol-type 1'-acetoxychavicol acetate (ACA) analogs as human leukemia cell-growth inhibitors based on quantitative structure-activity relationship (QSAR) analysis.  

PubMed

Benzhydrol-type analogs of 1'-acetoxychavicol acetate (ACA) were developed as inhibitors of human leukemia HL-60 cell growth based on quantitative structure-activity relationship (QSAR) analysis. An analog containing an anthracenyl moiety (8) was a potent inhibitor with the IC(50) value of 0.12 microM. PMID:18827399

Misawa, Takashi; Aoyama, Hiroshi; Furuyama, Taniyuki; Dodo, Kosuke; Sagawa, Morihiko; Miyachi, Hiroyuki; Kizaki, Masahiro; Hashimoto, Yuichi

2008-10-01

283

Structure-activity relationships of alloxan-like compounds derived from uric acid.  

PubMed Central

The diabetogenic activity of a range of alloxan-like compounds derived from uric acid has been investigated. The classes of derivatives were: 5-substituted-isouric acids; 4,5-disubstituted-4, 5-dihydrouric acids; 5-substituted-pseudouric acids; salts of dehydro-uramil hydrate; salts of dehydro-isouramil hydrate; alloxan derivatives. Compounds were tested by intravenous injection into rats and diabetogenic activity assessed by production of persistent hyperglycaemia and glycosuria. The only essential structural feature common to all active compounds was the presence of a quinonoid pyrimidine system or its hydrated equivalent. The presence of the five-membered ring of uric acid (or an opened form thereof) did not abolish and in some compounds enhanced diabetogenic activity.

Ashcroft, S. J.; Harrison, D. E.; Poje, M.; Rocic, B.

1986-01-01

284

Lipase-catalyzed preparation of optically active 1'-acetoxychavicol acetates and their structure-activity relationships in apoptotic activity against human leukemia HL-60 cells.  

PubMed

Structure-activity relationships of 1'-acetoxychavicol acetate (ACA) for apoptotic activity against human leukemia HL-60 cells were investigated using optically active ACA and various racemic ACA analogues. Natural-type (or with different acyl group) ACA showed a high apoptotic activity, but the ortho or meta isomers, 4-deacetoxy analogue, and the 2'-3' dehydrogenated derivative had no effect, or a weak activity. Optically active (R)- and (S)-ACA were prepared by a lipase-catalyzed esterification. Using a mixture of vinyl acetate-tetrahydrofuran (1:1 v/v) as a solvent at refluxing temperature, optically pure (R)- and (S)-ACA were obtained (99.7% ee and 99.1% ee, respectively). The apoptosis-inducing effects of both enantiomers were compared by means of an MTT assay and the detection of typical apoptotic phenomena (DNA fragmentation, caspase-3 activation, and PARP cleavage) and these two activities were almost equal. These results indicate that the essential moieties of ACA for apoptotic activity against HL-60 cells are both the presence of a 4-acetoxyl group and an unsaturated double bond between C-2' and C-3', and that the configuration at the 1'-position is unrelated to activity. PMID:16288877

Azuma, Hideki; Miyasaka, Keita; Yokotani, Tsuyoshi; Tachibana, Taro; Kojima-Yuasa, Akiko; Matsui-Yuasa, Isao; Ogino, Kenji

2005-11-08

285

Inhibition of human placental progesterone synthesis by estranes: a novel relationship of structure to activity.  

PubMed

The inhibition of human placental progesterone synthesis by estranes was investigated in vitro. Inhibition tended to increase with structural changes such as unsaturation of ring B, increased planarity and oxidation of the 17-hydroxyl to a ketone while biological "estrogenic" activity decreased. The finding that weak estrogens inhibit progesterone synthesis indicates a natural mechanism for control of hormonogenesis in the human placenta and a new approach to pharmacologic control of fertility. PMID:916672

Edwards, D P; Bransome, E D; O'Conner, J L; Braselton, W E

1977-09-01

286

Cationic membrane peptides: atomic-level insight of structure-activity relationships from solid-state NMR.  

PubMed

Many membrane-active peptides, such as cationic cell-penetrating peptides (CPPs) and antimicrobial peptides (AMPs), conduct their biological functions by interacting with the cell membrane. The interactions of charged residues with lipids and water facilitate membrane insertion, translocation or disruption of these highly hydrophobic species. In this review, we will summarize high-resolution structural and dynamic findings towards the understanding of the structure-activity relationship of lipid membrane-bound CPPs and AMPs, as examples of the current development of solid-state NMR (SSNMR) techniques for studying membrane peptides. We will present the most recent atomic-resolution structure of the guanidinium-phosphate complex, as constrained from experimentally measured site-specific distances. These SSNMR results will be valuable specifically for understanding the intracellular translocation pathway of CPPs and antimicrobial mechanism of AMPs, and more generally broaden our insight into how cationic macromolecules interact with and cross the lipid membrane. PMID:23108593

Su, Yongchao; Li, Shenhui; Hong, Mei

2012-10-30

287

Study of structure-activity relationship of enantiomeric, protonated and deprotonated forms of warfarin via vibrational spectroscopy and DFT calculations  

NASA Astrophysics Data System (ADS)

The structure-activity relationship of the anticoagulant drug warfarin were studied by studying two enantiomeric forms (S-form and R-form) of warfarin and its protonated as well as deprotonated structures in aqueous media using density functional theory (DFT). Theoretically computed Raman and IR spectra of all the computed structures were compared and their specific vibrational spectroscopic signatures were discussed. The percentage contributions of individual normal modes of warfarin, which provides direct evidence of the different molecular activity due to change in relative atomic position of atoms in molecule, were investigated through potential energy distribution (PED). The optimized energy and molecular electrostatic potential (MEP) maps show that the S-form of the drug molecules warfarin is energetically more stable than R-form and provides higher docking opportunity for the molecular binding with the receptors in the bio-systems.

Mishra, Alok; Srivastava, Sunil Kumar; Swati, D.

2013-09-01

288

Antimicrobial Photodynamic Therapy with Functionalized Fullerenes: Quantitative Structure-activity Relationships  

PubMed Central

Photosensitive dyes or photo sensitizers (PS) in combination with visible light and oxygen produce reactive oxygen species that kill cells in the process known as photodynamic therapy (PDT). Antimicrobial PDT employs PS that is selective for microbial cells and is a new treatment for infections. Most antimicrobial PS is based on tetrapyrrole or phenothiazinium structures that have been synthesized to carry quaternary cationic charges or basic amino groups. However we recently showed that cationic-substituted fullerene derivative were highly effective in killing a broad spectrum of microbial cells after illumination with white light. In the present report we compared a new group of synthetic fullerene derivatives that possessed either basic or quaternary amino groups as antimicrobial PS against Gram-positive (Staphylococcus aureus), Gram-negative bacteria (Escherichia coli) and fungi (Candida albicans). Quantitative structure-function relationships were derived with LogP and hydrophilic lipophilic balance parameters. Compounds with non-quaternary amino groups tended to form nanoaggregates in water and were only effective against S. aureus. The most important determinant of effectiveness was an increased number of quaternary cationic groups that were widely dispersed around the fullerene cage to minimize aggregation. S. aureus was most susceptible; E. coli was intermediate, while C. albicans was the most resistant species tested. The high effectiveness of antimicrobial PDT with quaternized fullerenes suggest they may have applications in treatment of superficial infections (for instance in wounds and burns) where light penetration into tissue is not problematic.

Mizuno, Kazue; Zhiyentayev, Timur; Huang, Liyi; Khalil, Sarwat; Nasim, Faria; Tegos, George P; Gali, Hariprasad; Jahnke, Ashlee; Wharton, Tim; Hamblin, Michael R

2011-01-01

289

Structure-activity relationship of an ozonide carboxylic acid (OZ78) against Fasciola hepatica.  

PubMed

In this paper, we describe the SAR of ozonide carboxylic acid OZ78 (1) as the first part of our search for a trematocidal synthetic peroxide drug development candidate. We found that relatively small structural changes to 1 resulted most commonly in loss of activity against Fasciola hepatica in vivo. A spiroadamantane substructure and acidic functional group (or ester prodrug) were required for activity. Of 26 new compounds administered at single 100 mg/kg oral doses to F. hepatica infected rats, 8 had statistically significant worm burden reductions, 7 were partially curative, and 1 (acylsulfonamide 6) was completely curative and comparable to 1 in flukicidal efficacy. This study also showed that the activity of 1 is peroxide-bond-dependent, suggesting that its flukicidal efficacy depends upon hemoglobin digestion in F. hepatica. PMID:20423101

Zhao, Qingjie; Vargas, Mireille; Dong, Yuxiang; Zhou, Lin; Wang, Xiaofang; Sriraghavan, Kamaraj; Keiser, Jennifer; Vennerstrom, Jonathan L

2010-05-27

290

Structure-activity relationship studies on unifiram (DM232) and sunifiram (DM235), two novel and potent cognition enhancing drugs.  

PubMed

Structure-activity relationships on two novel potent cognition enhancing drugs, unifiram (DM232, 1) and sunifiram (DM235, 2), are reported. Although none of the compounds synthesised reached the potency of the parent drugs, some fairly active compounds have been identified that may represent new leads to develop other cognition enhancing drugs. An interesting result of this research is the identification of two compounds (13 and 14) that are endowed with amnesing activity (the opposite of the activity of the original molecules) and are nearly equipotent to scopolamine. Moreover, two compounds of the series (5 and 6) were found endowed with analgesic activity on a rat model of neuropathic pain at the dose of 1 mg/kg. PMID:14697772

Scapecchi, Serena; Martini, Elisabetta; Manetti, Dina; Ghelardini, Carla; Martelli, Cecilia; Dei, Silvia; Galeotti, Nicoletta; Guandalini, Luca; Novella Romanelli, Maria; Teodori, Elisabetta

2004-01-01

291

Sesterterpenes as tubulin tyrosine ligase inhibitors. First insight of structure-activity relationships and discovery of new lead.  

PubMed

Twenty-four new sesterterpenes, compounds 1-24, were isolated from the aerial parts of Salvia dominica. Their structures were elucidated by 1D and 2D NMR experiments as well as ESIMS analysis and chemical methods. The evaluation of the biological activity of Salvia dominica sesterterpenes by means of a panel of chemical and biological approaches, including chemical proteomics, surface plasmon resonance (SPR) measurements, and biochemical assays were realized. Obtained results showed that 18 out of the 24 sesterterpene lactones isolated from Salvia dominica interact with tubulin-tyrosine ligase (TTL) an enzyme involved in the tyrosination cycle of the C-terminal of tubulin, and inhibit TTL activity in cancer cells. Besides, results of our studies provided an activity/structure relationship that can be used to design effective TTL inhibitors. PMID:19459643

Dal Piaz, Fabrizio; Vassallo, Antonio; Lepore, Laura; Tosco, Alessandra; Bader, Ammar; De Tommasi, Nunziatina

2009-06-25

292

Non-linear quantitative structure-activity relationship for adenine derivatives as competitive inhibitors of adenosine deaminase  

SciTech Connect

Logistic regression and artificial neural networks have been developed as two non-linear models to establish quantitative structure-activity relationships between structural descriptors and biochemical activity of adenosine based competitive inhibitors, toward adenosine deaminase. The training set included 24 compounds with known k {sub i} values. The models were trained to solve two-class problems. Unlike the previous work in which multiple linear regression was used, the highest of positive charge on the molecules was recognized to be in close relation with their inhibition activity, while the electric charge on atom N1 of adenosine was found to be a poor descriptor. Consequently, the previously developed equation was improved and the newly formed one could predict the class of 91.66% of compounds correctly. Also optimized 2-3-1 and 3-4-1 neural networks could increase this rate to 95.83%.

Sadat Hayatshahi, Sayyed Hamed [Department of Biophysics, Faculty of Science, Tarbiat Modares University, P.O. Box: 14115/175, Tehran (Iran, Islamic Republic of) ; Abdolmaleki, Parviz [Department of Biophysics, Faculty of Science, Tarbiat Modares University, P.O. Box: 14115/175, Tehran (Iran, Islamic Republic of) ]. E-mail: parviz@modares.ac.ir; Safarian, Shahrokh [Department of Biology, Faculty of Science, Tehran University, P.O. Box: 13155-6455, Tehran (Iran, Islamic Republic of) ; Khajeh, Khosro [Department of Biochemistry, Faculty of Science, Tarbiat Modares University, P.O. Box: 14115/175, Tehran (Iran, Islamic Republic of)

2005-12-16

293

An in vitro study of the structure-activity relationships of sulfated polysaccharide from brown algae to its antioxidant effect.  

PubMed

In this paper, the structure-activity relationships of chemically modified uronic acid polymer fragments from brown algae with regard to their antioxidant effects on H2O2-damaged lymphocyte were studied. The results indicated that the most potent antioxidant activity was obtained from the sulfated polysaccharide with ratio of mannuronate blocks (M-blocks) to guluronate blocks (G-blocks) of 3 to 1 and carboxyl residue unesterified. The sulfated G-blocks with esterified carboxyl residue also prevented lymphocyte from injury. However, the sulfated G-blocks bearing unesterified carboxyl residue hardly exerted antioxidant activity. These findings suggested that both M-blocks and esterified carboxyl residue were determinant structures in preventing lymphocyte from being oxidized by H202, indicating that the existence of M-blocks was more important in scavenging free radicals. PMID:11783590

Hu, J F; Gen, M Y; Zhang, J T; Jiang, H D

2001-01-01

294

Avenanthramides in oats (Avena sativa L.) and structure-antioxidant activity relationships.  

PubMed

Eight avenanthramides, amides of anthranilic acid (1) and 5-hydroxyanthranilic acid (2), respectively, and the four cinnamic acids p-coumaric (p), caffeic (c), ferulic (f), and sinapic (s) acid, were synthesized for identification in oat extracts and for structure-antioxidant activity studies. Three compounds (2p, 2c, and 2f) were found in oat extracts. As assessed by the reactivity toward 1,1-diphenyl-2-picrylhydrazyl (DPPH), all avenanthramides except 1p showed activity. Initially, the antioxidant activity of the avenanthramides decreased in a similar order as for the corresponding cinnamic acids, that is: sinapic > caffeic > ferulic > p-coumaric acid. The avenanthramides derived from 2 were usually slightly more active than those derived from 1. All avenanthramides inhibited azo-initiated peroxidation of linoleic acid. 1c and 1s were initially the most effective compounds. The relative order of antioxidant activities was slightly different for the DPPH and the linoleic acid assays run in methanol and chlorobenzene, respectively. PMID:12537428

Bratt, Katarina; Sunnerheim, Kerstin; Bryngelsson, Susanne; Fagerlund, Amelie; Engman, Lars; Andersson, Rolf E; Dimberg, Lena H

2003-01-29

295

Structure-activity relationships of neuropeptide FF: role of C-terminal regions.  

PubMed

A structure-activity study was carried out to determine the importance of the C-terminal amino acids of the octapeptide Neuropeptide FF (NPFF) in binding and agonistic activity. Affinities of NPFF analogues were tested toward NPFF receptors of the rat spinal cord and the human NPFF2 receptors transfected in CHO cells. The activities of these analogues were evaluated by their ability to both inhibit adenylate cyclase in NPFF2 receptor transfected CHO cells and to reverse the effect of nociceptin on acutely dissociated rat dorsal raphe neurons. The substitutions of Phenylalanine8 by a tyrosine, phenylglycine or homophenylalanine were deleterious for high affinity. Similarly, the replacement of Arginine7 by a lysine or D. Arginine induces a loss in affinity. The pharmacological characterization showed that the presence of the amidated Phe8 and Arg7 residues are also extremely critical for activation of anti-opioid effects on dorsal raphe neurons. The sequence of the C-terminal dipeptide seems also to be responsible for the high affinity and the activity on human NPFF2 receptors. The results support the view that a code messaging the molecular interaction toward NPFF-receptors is expressed in the C-terminal region of these peptides but the N-terminal segment is important to gain very high affinity. PMID:11514031

Mazarguil, H; Gouardères, C; Tafani, J A; Marcus, D; Kotani, M; Mollereau, C; Roumy, M; Zajac, J M

2001-09-01

296

The relationship between molecular structure and biological activity of alkali metal salts of vanillic acid: spectroscopic, theoretical and microbiological studies.  

PubMed

In this paper we investigate the relationship between molecular structure of alkali metal vanillate molecules and their antimicrobial activity. To this end FT-IR, FT-Raman, UV absorption and (1)H, (13)C NMR spectra for lithium, sodium, potassium, rubidium and caesium vanillates in solid state were registered, assigned and analyzed. Microbial activity of studied compounds was tested against Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, Proteus vulgaris, Bacillus subtilis and Candida albicans. In order to evaluate the dependence between chemical structure and biological activity of alkali metal vanillates the statistical analysis was performed for selected wavenumbers from FT-IR spectra and parameters describing microbial activity of vanillates. The geometrical structures of the compounds studied were optimized and the structural characteristics were determined by density functional theory (DFT) using at B3LYP method with 6-311++G** as basis set. The obtained statistical equations show the existence of correlation between molecular structure of vanillates and their biological properties. PMID:22341494

?wis?ocka, Renata; Piekut, Jolanta; Lewandowski, W?odzimierz

2012-02-01

297

Structure-Activity Relationship in Nanostructured Copper-Ceria-Based Preferential CO Oxidation Catalysts  

SciTech Connect

Two series of nanostructured oxidized copper-cerium catalysts with varying copper loadings, and prepared, respectively, by impregnation of ceria and by coprecipitation of the two components within reverse microemulsions, have been characterized in detail at structural and electronic levels by X-ray diffraction (XRD), Raman spectroscopy, high-resolution electron microscopy (HREM), X-ray energy dispersive spectroscopy (XEDS), X-ray photoelectron spectroscopy (XPS) (including Ar{sup +}-sputtering), and X-ray absorption fine structure (XAFS). These results have been correlated with analysis of their catalytic properties for preferential oxidation of CO in a H{sub 2}-rich stream (CO-PROX), complemented by Operando-DRIFTS. A relevant difference between the two series of catalysts concerns the nature of the support for the surface-dispersed copper oxide entities, which is essentially ceria for the samples prepared by impregnation and a Ce-Cu mixed oxide for those prepared by microemulsion-coprecipitation. The existence of copper segregation in the form of copper oxide or copper-enriched Cu-Ce mixed oxides for the latter type of samples is uniquely revealed by nanoprobe XEDS and XPS Ar{sup +}-sputtering experiments. The CO oxidation activity under CO-PROX conditions is correlated to the degree of support-promoted reduction achieved by the dispersed copper oxide particles under reaction conditions. Nevertheless, catalysts which display higher CO oxidation activity are generally more efficient also for the undesired H{sub 2} oxidation reaction. The balance between both reactions results in differences in the CO-PROX activity between the two series of catalysts which are examined on the basis of the structural differences found.

Gamarra,D.; Munuera, G.; Hungria, A.; Fernandez-Garcia, M.; Conesa, J.; Midgley, P.; Wang, X.; Hanson, J.; Rodriguez, J.; Martinez-Arias, A.

2007-01-01

298

Structure-activity relationships of SSAO/VAP-1 arylalkylamine-based substrates.  

PubMed

Semicarbazide-sensitive amine oxidase/vascular adhesion protein-1 (SSAO/VAP-1) substrates show insulin-mimetic effects and are therefore potentially valuable molecules for the treatment of diabetes mellitus. Herein we review several structural and electronic aspects of SSAO arylalkylamine-based substrates. Two main modifications directly affect amine oxidase (AO) activity: 1) variation in ring substitution modulates the biological activity of the arylalkylamine ligand by converting a substrate into a substrate-like inhibitor, and 2) variation in the number of methylene units between the aromatic ring and the ammonium groups of the arylalkylamine substrates dramatically alters the oxidation rate between species. Furthermore, we review relevant information about mammalian SSAO/VAP-1 substrate selectivity and specificity over monoamine oxidases (MAOs). PMID:19266512

Yraola, Francesc; Zorzano, Antonio; Albericio, Fernando; Royo, Miriam

2009-04-01

299

Structure-Function Relationships in [FeFe]-Hydrogenase Active Site Maturation*  

PubMed Central

Since the discovery that, despite the active site complexity, only three gene products suffice to obtain active recombinant [FeFe]-hydrogenase, significant light has been shed on this process. Both the source of the CO and CN? ligands to iron and the assembly site of the catalytic subcluster are known, and an apo structure of HydF has been published recently. However, the nature of the substrate(s) for the synthesis of the bridging dithiolate ligand to the subcluster remains to be established. From both spectroscopy and model chemistry, it is predicted that an amine function in this ligand plays a central role in catalysis, acting as a base in the heterolytic cleavage of hydrogen.

Nicolet, Yvain; Fontecilla-Camps, Juan C.

2012-01-01

300

Structure-activity relationship studies of the two-component lantibiotic haloduracin.  

PubMed

The lantibiotic haloduracin consists of two posttranslationally processed peptides, Halalpha and Halbeta, which act in synergy to provide bactericidal activity. An in vitro haloduracin production system was used to examine the biological impact of disrupting individual thioether rings in each peptide. Surprisingly, the Halalpha B ring, which contains a highly conserved CTLTXEC motif, was expendable. This motif has been proposed to interact with haloduracin's predicted target, lipid II. Exchange of the glutamate residue in this motif for alanine or glutamine completely abolished antibacterial activity. This study also established that Halalpha-Ser26 and Halbeta-Ser22 escape dehydration, requiring revision of the Halbeta structure previously proposed. Extracellular proteases secreted by the producer strain can remove the leader peptide, and the Halalpha cystine that is dispensable for bioactivity protects Halalpha from further proteolytic degradation. PMID:18940665

Cooper, Lisa E; McClerren, Amanda L; Chary, Anita; van der Donk, Wilfred A

2008-10-20

301

Structure-Activity Relationship Studies of the Two-Component Lantibiotic Haloduracin  

PubMed Central

Summary The lantibiotic haloduracin consists of two post-translationally processed peptides, Hal? and Hal?, that act in synergy to provide bactericidal activity. An in vitro haloduracin production system was utilized to examine the biological impact of disrupting individual thioether rings in each peptide. Surprisingly, the Hal? B-ring, which contains a highly conserved CTLTXEC motif, was expendable. This motif has been proposed to interact with haloduracin’s predicted target, lipid II. Exchange of the glutamate residue in this motif for alanine or glutamine did completely abolish antibacterial activity. This study also established that Hal?-Ser26 and Hal?-Ser22 escape dehydration, requiring revision of the Hal? structure previously proposed. Extracellular proteases secreted by the producer strain can remove the leader peptide, and the Hal? cystine that is dispensable for bioactivity protects Hal? from further proteolytic degradation.

Cooper, Lisa E.; McClerren, Amanda L; Chary, Anita; van der Donk, Wilfred A.

2008-01-01

302

Total synthesis of (-)-zampanolide and structure-activity relationship studies on (-)-dactylolide derivatives.  

PubMed

A new total synthesis of the marine macrolide (-)-zampanolide (1) and the structurally and stereochemically related non-natural levorotatory enantiomer of (+)-dactylolide (2), that is, ent-2, has been developed. The synthesis features a high-yielding, selective intramolecular Horner-Wadsworth-Emmons (HWE) reaction to close the 20-membered macrolactone ring of 1 and ent-2. The ?-keto phosphonate/aldehyde precursor for the ring-closure reaction was obtained by esterification of a ?-diethylphosphono carboxylic acid fragment and a secondary alcohol fragment incorporating the THP ring that is embedded in the macrocyclic core structure of 1 and ent-2. THP ring formation was accomplished through a segment coupling Prins-type cyclization. Employing the same overall strategy, 13-desmethylene-ent-2 as well as the monocyclic desTHP derivatives of 1 and ent-2 were prepared. Synthetic 1 inhibited human cancer cell growth in vitro with nM IC(50) values, while ent-2, which lacks the diene-containing hemiaminal-linked side chain of 1, is 25- to 260-fold less active. 13-Desmethylene-ent-2 as well as the reduced versions of ent-2 and 13-desmethylene-ent-2 all showed similar cellular activity as ent-2 itself. The same activity level was attained by the monocyclic desTHP derivative of 1. Oxidation of the aldehyde functionality of ent-2 gave a carboxylic acid that was converted into the corresponding N-hexyl amide. The latter showed only ?M antiproliferative activity, thus being several hundred-fold less potent than 1. PMID:23136113

Zurwerra, Didier; Glaus, Florian; Betschart, Leo; Schuster, Julia; Gertsch, Jürg; Ganci, Walter; Altmann, Karl-Heinz

2012-11-07

303

Macrobenthos community structure and trophic relationships within active and inactive Pacific hydrothermal sediments  

NASA Astrophysics Data System (ADS)

Hydrothermal fluids passing through sediments create a habitat hypothesized to influence the community structure of infaunal macrobenthos. Here we characterize the density, biomass, species composition, diversity, distributions, lifestyle, and nutritional sources of macroinfauna in hydrothermal sediments in NE and SW Pacific settings, and draw comparisons in search of faunal attributes characteristic of this habitat. There is increasing likelihood that seafloor massive sulfide deposits, associated with active and inactive hydrothermal venting, will be mined commercially. This creates a growing imperative for a more thorough understanding of the structure, dynamics, and resilience of the associated sediment faunas, and has stimulated the research presented here. Macrobenthic assemblages were studied at Manus Basin (1430-1634 m, Papua New Guinea [PNG]) as a function of location (South Su vs. Solwara 1), and hydrothermal activity (active vs. inactive), and at Middle Valley (2406-2411 m, near Juan de Fuca Ridge) as a function of habitat (active clam bed, microbial mat, hot mud, inactive background sediment). The studies conducted in PNG formed part of the environmental impact assessment work for the Solwara 1 Project of Nautilus Minerals Niugini Limited. We hypothesized that hydrothermally active sites should support (a) higher densities and biomass, (b) greater dominance and lower diversity, (c) a higher fraction of deposit feeders, and (d) greater isotopic evidence for chemosynthetic food sources than inactive sites. Manus Basin macrofauna generally had low density (<1000 ind. m -2) and low biomass (0.1-1.07 g m -2), except for the South Su active site, which had higher density (3494 ind. m -2) and biomass (11.94 g m -2), greater dominance (R1D=76%), lower diversity and more spatial (between-core) homogeneity than the Solwara 1 and South Su inactive sites. Dominant taxa at Manus Basin were Spionidae ( Prionospio sp.) in active sediments, and tanaids and deposit-feeding nuculanoid bivalves in active and inactive sediments. At Middle Valley, hot mud sediments supported few animals (1011 ind m -2) and low biomass (1.34 g m -2), while active clam bed sediments supported a high-density (19,984 ind m -2), high-biomass (4.46 g m -2), low-diversity assemblage comprised of largely orbiniid and syllid polychaetes. Microbial mat sediments had the most diverse assemblage (mainly orbiniid, syllid, dorvilleid, and ampharetid polychaetes) with intermediate densities (8191 ind m -2) and high biomass (4.23 g m -2). Fauna at both Manus Basin active sites had heavy ? 13C signatures (-17‰ to -13‰) indicative of chemosynthetic, TCA-cycle microbes at the base of the food chain. In contrast, photosynthesis and sulfide oxidation appear to fuel most of the fauna at Manus Basin inactive sites (? 13C=-29‰ to -20‰) and Middle Valley active clam beds and microbial mats (? 13C=-36‰ to -20‰). The two hydrothermal regions, located at opposite ends of the Pacific Ocean, supported different habitats, sharing few taxa at the generic or family level, but both exhibited elevated infaunal density and high dominance at selected sites. Subsurface-deposit feeding and bacterivory were prevalent feeding modes. Both the Manus Basin and Middle Valley assemblages exhibit significant within-region heterogeneity, apparently conferred by variations in hydrothermal activity and associated biogenic habitats.

Levin, Lisa A.; Mendoza, Guillermo F.; Konotchick, Talina; Lee, Raymond

2009-09-01

304

Quantitative structure-activity relationship (QSAR) studies for predicting activation of the ryanodine receptor type 1 channel complex (RyR1) by polychlorinated biphenyl (PCB) congeners  

Microsoft Academic Search

A quantitative structure-activity relationship (QSAR) was developed to predict the congener specific ryanodine receptor type RyR1 activity of all 209 polychlorinated biphenyl (PCB) congeners. A three-variable QSAR equation was obtained via stepwise forward linear regression on an unsupervised forward selection reduced data set from an initial database. Application of the QSAR towards predicting EC2x values for all 209 PCB congeners

Sierra Rayne; Kaya Forest

2010-01-01

305

Semisynthesis and quantitative structure-activity relationship (QSAR) study of some cholesterol-based hydrazone derivatives as insecticidal agents.  

PubMed

In continuation of our program aimed at the discovery and development of natural-product-based insecticidal agents, four series of novel cholesterol-based hydrazone derivatives were synthesized, and their insecticidal activity was tested against the pre-third-instar larvae of oriental armyworm, Mythimna separata (Walker) in vivo at 1mg/mL. All the derivatives showed the better insecticidal activity than their precursor cholesterol. Quantitative structure-activity relationship (QSAR) model demonstrated that six descriptors such as RDF085v, Mor06u, Mor11u, Dv, HATS0v and H-046, are likely to influence the insecticidal activity of these compounds. Among them, two important ones are the Mor06u and RDF085v. PMID:23891182

Yang, Chun; Shao, Yonghua; Zhi, Xiaoyan; Huan, Qu; Yu, Xiang; Yao, Xiaojun; Xu, Hui

2013-07-10

306

Hepatoprotection of sesquiterpenoids: A quantitative structure-activity relationship (QSAR) approach.  

PubMed

The relative hepatoprotection effect of fifteen sesquiterpenoids, commonly found in plants and plant-derived foods and beverages was assessed. Endogenous lipid peroxidation (assay A) and induced lipid peroxidation (assay B) were evaluated in liver homogenates from Wistar rats by the thiobarbituric acid reactive species test. Sesquiterpenoids with different chemical structures were tested: trans,trans-farnesol, cis-nerolidol, (-)-?-bisabolol, trans-?-farnesene, germacrene D, ?-humulene, ?-caryophyllene, isocaryophyllene, (+)-valencene, guaiazulene, (-)-?-cedrene, (+)-aromadendrene, (-)-?-neoclovene, (-)-?-copaene, and (+)-cyclosativene. Ascorbic acid was used as a positive antioxidant control. With the exception of ?-humulene, all the sesquiterpenoids under study (1mM) were effective in reducing the malonaldehyde levels in both endogenous and induced lipid peroxidation up to 35% and 70%, respectively. The 3D-QSAR models developed, relating the hepatoprotection activity with molecular properties, showed good fit (Radj(2) 0.819 and 0.972 for the assays A and B, respectively) with good prediction power (Q(2)>0.950 and SDEP<2%, for both models A and B). A network of effects associated with structural and chemical features of sesquiterpenoids such as shape, branching, symmetry, and presence of electronegative fragments, can modulate the hepatoprotective activity observed for these compounds. PMID:24176316

Vinholes, Juliana; Rudnitskaya, Alisa; Gonçalves, Pedro; Martel, Fátima; Coimbra, Manuel A; Rocha, Sílvia M

2013-09-13

307

Diversity among microbial cyclic lipopeptides: iturins and surfactins. Activity-structure relationships to design new bioactive agents.  

PubMed

A prominent group of bioactive lipopeptides produced by Bacillus species is constituted by iturins, surfactins and lichenysins. Interest in such substances results in their exceptional surfactant power, and their valuable antifungal, antibacterial, antitumoral and anti-Mycoplasma properties. As is typical for peptidic secondary-metabolites synthesized by the polyenzymic pathway, they are produced as mixtures of components varying in the peptidic and/or in the lipidic structure. In the context of structure-activity relationships, it is possible to take advantage of the adaptability of the biosynthesis system by systematically adding selected amino acids in the culture medium of the producing bacterium. When an amino acid is used as the sole nitrogen source, it is inserted directly into selected positions of the peptide sequence, thus amplifying the original structural microheterogeneity via a production of variants. This method revealed very efficient for increasing the amounts of preexisting variants and for building new variants of surfactins and lichenysins but totally inefficient with iturins. In this group, the peptidic diversity strictly depends on the selected strain. So far the screening remained the only method to discover new iturins. Another interesting peculiarity is the common occurrence in a single strain of two lipopeptides with different core structures such as surfactins and iturins. Taken together, these features led to an extensive metabolite pattern. Besides, engineered variants and chemical derivatives enlarged the array of available molecules. Despite the high degree of chemical similarity, the separation of variants and/or homologues was successfully achieved by reversed-phase HPLC leading to well-separated compounds ideally suited to investigation of structure-activity relationships. Improved physical techniques such as 2D-NMR and mass spectrometry allowed to describe efficiently and rapidly the composition of cyclic lipopeptides even in mixtures containing several variants. From NMR, the 3D structure and dynamics gave crucial data for fine structure-activity relationships as well as for understanding of the properties at the membrane and/or at the air/water interface. Here the role of residues was identified in the context of hydrophobic and electrostatic interactions that play a leader role. Such a comprehensive approach, based on both structural and biosynthesis knowledge, opened the way to rational design for enhanced properties and its validity was confirmed with 10 fold higher surfactant efficacy. PMID:14529379

Bonmatin, Jean-Marc; Laprévote, Olivier; Peypoux, Françoise

2003-09-01

308

Synthesis and structure-activity relationship of N-(cinnamyl) chitosan analogs as antimicrobial agents.  

PubMed

The current study focuses on the preparation of new N-(cinnamyl) chitosan derivatives as antimicrobial agents against nine types of crop-threatening pathogens. Chitosan was reacted with a set of aromatic cinnamaldehyde analogs by reductive amination involving formation of the corresponding imines, followed by reduction with sodium borohydride to produce N-(cinnamyl) chitosan derivatives. The structural characterization was confirmed by (1)H and (13)C NMR spectroscopy and the degrees of substitution ranged from 0.08 to 0.28. The antibacterial activity was evaluated in vitro by minimum inhibitory concentration (MIC) against Agrobacterium tumefaciens and Erwinia carotovora. A higher inhibition activity was obtained by N-(?-methylcinnamyl) chitosan with MIC 1275 and 1025 mg/L against A. tumefaciens and E. carotovora, respectively followed by N-(o-methoxycinnamyl) chitosan (MIC=1925 and 1550 mg/L, respectively). The antifungal assessment was evaluated in vitro by mycelial radial growth technique against Alternaria alternata, Botrytis cinerea, Botryodiplodia theobromae, Fusarium oxysporum, Fusarium solani, Pythium debaryanum and Phytophthora infestans. N-(o-methoxycinnamyl) chitosan showed the highest antifungal activity among the tested compounds against the airborne fungi A. alternata, B. cinerea, Bd. theobromae and Ph. infestans with EC?? of 672, 796, 980 and 636 mg/L, respectively. However, N-(p-N-dimethylaminocinnamyl) chitosan was the most active against the soil born fungi F. oxysporum, F. solani and P. debaryanum (EC50=411, 566 and 404 mg/L, respectively). On the other hand, the chitosan derivatives caused significant reduction in spore germination of A. alternata, B. cinerea, F. oxysporum and F. solani compared to chitosan and the reduction in spore germination was higher than that of the mycelia inhibition. The synthesis and characterization of new chitosan derivatives are ongoing in our laboratory aiming to obtain derivatives with higher antimicrobial activities and used as safe alternatives to harmful microbicides. PMID:23511055

Badawy, Mohamed E I; Rabea, Entsar I

2013-03-16

309

Bis-phosphonium salts of pyridoxine: The relationship between structure and antibacterial activity.  

PubMed

A series of 23 novel bis-phosphonium salts based on pyridoxine were synthesized and their antibacterial activities were evaluated in vitro. All compounds were inactive against gram-negative bacteria and exhibited the structure-dependent activity against gram-positive bacteria. The antibacterial activity enhanced with the increase in chain length at acetal carbon atom in the order n-Pr>Et>Me. Further increasing of length and branching of alkyl chain leads to the reduction of antibacterial activity. Replacement of the phenyl substituents at the phosphorus atoms in 5,6-bis(triphenylphosphonio(methyl))-2,2,8-trimethyl-4H-[1,3]-dioxino[4,5-c]pyridine dichloride (compound 1) with n-butyl, m-tolyl or p-tolyl as well as chloride anions in the compound 1 with bromides (compound 14a) increased the activity against Staphylococcus aureus and Staphylococcus epidermidis up to 5times (MICs=1-1.25?g/ml). But in practically all cases chemical modifications of compound 1 led to the increase of its toxicity for HEK-293 cells. The only exception is compound 5,6-bis[tributylphosphonio(methyl)]-2,2,8-trimethyl-4H-[1,3]dioxino[4,5-c]pyridine dichloride (10a) which demonstrated lower MIC values against S. aureus and S. epidermidis (1?g/ml) and lower cytotoxicity on HEK-293 cells (CC50=200?g/ml). Compound 10a had no significant mutagenic and genotoxic effects and was selected for further evaluation. It should be noted that all bis-phosphonium salt based on pyridoxine were much more toxic than vancomycin. PMID:24139168

Pugachev, Mikhail V; Shtyrlin, Nikita V; Sapozhnikov, Sergey V; Sysoeva, Lubov P; Iksanova, Alfiya G; Nikitina, Elena V; Musin, Rashid Z; Lodochnikova, Olga A; Berdnikov, Eugeny A; Shtyrlin, Yurii G

2013-10-01

310

Minimal-length short hairpin RNAs: The relationship of structure and RNAi activity  

PubMed Central

Small hairpin RNAs (shRNAs) are widely used in RNAi studies and typically consist of a stem of 19–29 base pairs (bp), a loop of at least 4 nucleotides (nt), and a dinucleotide overhang at the 3? end. Compared with shRNAs with 21–29 bp stems, we have found that shRNAs with 19-bp or shorter stems (sshRNAs) possess some unique structure–activity features that depend on whether the antisense strand is positioned 5? or 3? to the loop (L- or R-type sshRNAs, respectively). L sshRNAs can have IC50s in the very low picomolar range, and sshRNAs with nominal loop sizes of 1 or 4 nt were at least as active as those with longer loops. L sshRNAs remained highly potent even when the 3? end of the antisense strand was directly linked with the 5? end of the sense strand. In this case, the sense strand can be shorter than the antisense strand, and the loop can be formed entirely by the 3? end of the antisense strand. Monomer sshRNAs are not processed by recombinant Dicers in vitro. Although they can form dimers that are sometimes Dicer substrates, their RNAi activity is not dependent on the formation of such structures. Our findings have implications for the mechanism of action of sshRNAs, and the ability to design highly potent shRNAs with minimal length is encouraging for the prospects of the therapeutic use of direct-delivered shRNAs.

Ge, Qing; Ilves, Heini; Dallas, Anne; Kumar, Pavan; Shorenstein, Joshua; Kazakov, Sergei A.; Johnston, Brian H.

2010-01-01

311

Structure-Activity Relationships of Lipopolysaccharide Sequestration in N-Alkylpolyamines  

PubMed Central

We have previously shown that simple N-acyl or N-alkyl polyamines bind to and sequester Gram-negative bacterial lipopolysaccharide, affording protection against lethality in animal models of endotoxicosis. Several iterative design-and-test cycles of SAR studies, including high-throughput screens, had converged on compounds with polyamine scaffolds which have been investigated extensively with reference to the number, position, and length of acyl or alkyl appendages. However, the polyamine backbone itself had not been explored sufficiently, and it was not known if incremental variations on the polymethylene spacing would affect LPS-binding and neutralization properties. We have now systematically explored the relationship between variously elongated spermidine [NH2-(CH2)3-NH-(CH2)4-NH2] and norspermidine [NH2-(CH2)3-NH-(CH2)3-NH2] backbones, with the N-alkyl group being held constant at C16 in order to examine if changing the spacing between the inner secondary amines may yield additional SAR information. We find that the norspermine-type compounds consistently showed higher activity compared to corresponding spermine homologues.

Shrestha, Anurupa; Sil, Diptesh; Malladi, Subbalakshmi S.; Warshakoon, Hemamali J.

2013-01-01

312

StructureActivity Relationships Derived by Machine Learning: The Use of Atoms and their Bond Connectivities to Predict Mutagenicity by Inductive Logic Programming  

Microsoft Academic Search

We present a general approach to forming structure-activity relationships (SARs). This approach is based on representing chemical structure by atoms and their bond connectivities in combination with the inductive logic programming (ILP) algorithm PROGOL. Existing SAR methods describe chemical structure by using attributes which are general properties of an object. It is not possible to map chemical structure directly to

Ross D. King; Stephen H. Muggleton; Ashwin Srinivasan; Michael J. E. Sternberg

1996-01-01

313

Pharmacophore modeling and 3D quantitative structure-activity relationship analysis of febrifugine analogues as potent antimalarial agent.  

PubMed

Febrifugine and its derivatives are effective against Plasmodium falciparum. Using PHASE algorithm, a five-point pharmacophore model with two hydrogen bond acceptor (A), one positively ionizable (P) and two aromatic rings (R), was developed to derive a predictive ligand-based statistically significant 3D-quantitative structure-activity relationship (QSAR) model (r(2) = 0.972, SD = 0.3, F = 173.4, Q(2) = 0.712, RMSE = 0.3, Person-R = 0.94, and r(2) pred = 0.8) to explicate the structural attributes crucial for antimalarial activity. The developed pharmacophore model and 3D QSAR model can be a substantial tool for virtual screening and related antimalarial drug discovery research. PMID:23662282

Sen, Debanjan; Chatterjee, Tapan Kumar

2013-01-01

314

Structure-activity relationships of nociceptin and related peptides: comparison with dynorphin A.  

PubMed

Nociceptin and its receptor (OP(4)) share sequence homologies with the opioid peptide ligand dynorphin A and its receptor OP(2). Cationic residues in the C-terminal sequence of both peptides seem to be required for selective receptor occupation, but the number and the distribution of these basic residues are different and quite critical. Both receptors are presumably activated by the peptides N-terminal sequence (Xaa-Gly Gly-Phe, where Xaa = Phe or Tyr); however, although OP(4) requires Phe(4) as a determinant pharmacophore, OP(2) requires Tyr(1) as do the other opioid receptors. An extensive structure-activity analysis of the N-terminal tetrapeptide has led to conclude that the presence of aromatic residues in position one and four, preferably Phe, as well as the distance between Phe(1) and Phe(4) are extremely critical for occupation and activation of OP(4) in contrast with other opioid receptors (e.g. OP(1), OP(3), OP(2)). Modification of distance between the side chains of Phe(1) and Phe(4) (as obtained with Nphe(1) substitution in both NC and NC(1-13)-NH(2)) and/or conformational orientation of Phe(1) (as in Phe(1)psi(CH(2)-NH)-Gly(2)) has brought to discovery of pure antagonist ([Nphe(1)]-NC(1-13)-NH(2)) and a partial agonist ([Phe(1) psi(CH(2)-NH)-Gly(2)]-NC(1-13)-NH(2)), which have allowed us to characterize and classify the OP(4) receptor in several species. Thus, although antagonist activities at the OP(4) receptor are obtained by chemical modification of Phe(1)-Gly(2) peptide bond or by a shift of Phe(1) side chain of NC peptides, antagonism at the OP(2) receptor requires the diallylation of the N-terminal amino function, for instance, of dynorphin A. These considerations support the interpretation that the two systems nociceptin/OP(4) and dynorphin A/OP(2) are distinct pharmacological entities that differs in both their active sites (Tyr(1) for Dyn A and Phe(4) for NC) and the number and position of cationic residues in the C-terminal portions of the molecules. The chemical features of novel OP(4) receptor ligands either pseudopeptides obtained by combinatorial library screening or molecules of nonpeptide structure are reported and discussed in comparison with NC and NC related peptides. PMID:10998526

Guerrini, R; Calo', G; Rizzi, A; Bigoni, R; Rizzi, D; Regoli, D; Salvadori, S

2000-07-01

315

Structure-activity relationships in human Toll-like receptor 2-specific monoacyl lipopeptides.  

PubMed

Toll-like receptor 2-agonistic lipopeptides typified by S-[2,3-bis(palmitoyloxy)-(2RS)-propyl]-R-cysteinyl-S-serine (PAM(2)CS) compounds are potential vaccine adjuvants. We had previously determined that at least one acyl group of optimal length (C(16)) and an appropriately orientated ester carbonyl group is essential for TLR2-agonistic activity. We now show that these structurally simpler analogues display agonistic activities with human, but not murine, TLR2. SAR studies on the monoacyl derivatives show that the optimal acyl chain length is C(16), and aryl substituents are not tolerated. A variety of alkyl and acyl substituents on the cysteine amine were examined. All N-alkyl derivatives were inactive. In contradistinction, short-chain N-acyl analogues were found to be highly active, with a clear dependence on the chain length. A cysteine N-acetyl analogue was found to be the most potent (EC(50): 1 nM), followed by the N-butyryl analogue. The N-acetyl analogue is human TLR2-specific, with its potency comparable to that of PAM(2)CS. PMID:22385476

Salunke, Deepak B; Shukla, Nikunj M; Yoo, Euna; Crall, Breanna M; Balakrishna, Rajalakshmi; Malladi, Subbalakshmi S; David, Sunil A

2012-03-15

316

Bioactivity screening of partially desulfated low-molecular-weight heparins: a structure/activity relationship study.  

PubMed

A series of size-defined low-molecular-weight heparins were generated by regioselective chemical modifications and profiled for their in vitro and in vivo activities. The compounds displayed reduced anti-coagulant activity, demonstrated varying affinities toward angiogenic growth factors (fibroblast growth factor-2, vascular endothelial growth factor and stromal cell-derived factor-1?), inhibited the P-selectin/P-selectin glycoprotein ligand-1 interaction and, notably, exhibited anti-tumor efficacy in a murine melanoma experimental metastasis model. Our results demonstrate that modulating specific sequences, especially the N-domains (-NS or -NH(2) or -NHCOCH(3)) in these polysaccharide sequences, has a major impact on the participation in a diverse range of biological activities. These results also suggest that the 6-O-sulfates, but not the 2-O-sulfates, critically affect the binding of a desulfated derivative to certain angiogenic proteins as well as its ability to inhibit P-selectin-mediated B16F10 melanoma metastases. Furthermore, N-desulfation followed by N-acetylation regenerates the affinity/inhibition properties to different extents in all the compounds tested in the in vitro assays. This systematic study lays a conceptual foundation for detailed structure function elucidation and will facilitate the rational design of targeted heparan sulfate proteoglycan-based anti-metastatic therapeutic candidates. PMID:21515908

Roy, Sucharita; Lai, Hsuanchi; Zouaoui, Radouane; Duffner, Jay; Zhou, He; P Jayaraman, Lakshmi; Zhao, Ganlin; Ganguly, Tanmoy; Kishimoto, Takashi K; Venkataraman, Ganesh

2011-04-22

317

Structure-Activity Relationship of New Antituberculosis Agents Derived from Oxazoline and Oxazole Esters  

PubMed Central

During the syntheses and studies of natural iron chelators (mycobactins), we serendipitously discovered that a simple, small molecule, oxazoline-containing intermediate 3 displayed surprising anti-tuberculosis activity (MIC of 7.7 µM, average). Herein we report elaboration of SAR around this hit as well as the syntheses and evaluation of a hundred oxazoline- and oxazole-containing compounds derived from an efficient three step process: 1) formation of ?-hydroxy amides with serine or threonine; 2) cyclization to afford oxazolines; and 3) dehydration to give the corresponding oxazoles. A number of compounds prepared by this method were shown to possess impressive activity against M. tuberculosis, extremely low toxicity and therefore high therapeutic indexes, as well as activity against even the more recalcitrant non-replicating form of M. tuberculosis. The uniqueness of their structures and their simplicity should allow them to be further optimized to meet ADME (absorption, distribution, metabolism, excretion) requirements. The syntheses of eight of the most potent in vitro compounds were scaled up and the compounds were tested in an in vivo mouse infection model to evaluate their efficacy before engaging upon more elaborate compound design and optimization.

Moraski, Garrett C.; Chang, Mayland; Villegas-Estrada, Adriel; Franzblau, Scott G.; Mollmann, Ute; Miller, Marvin J.

2010-01-01

318

Structure-Activity Relationships in Human Toll-like Receptor 2-Specific Monoacyl Lipopeptides  

PubMed Central

Toll-like receptor 2-agonistic lipopeptides typified by S-[2,3-bis(palmitoyloxy)-(2RS)-propyl]-R-cysteinyl-S-serine (PAM2CS) compounds are potential vaccine adjuvants. We had previously determined that at least one acyl group of optimal length (C16) and an appropriately orientated ester carbonyl group is essential for TLR2-agonistic activity. We now show that these structurally simpler analogues display agonistic activities with human, but not murine TLR2. SAR studies on the monoacyl derivatives show that the optimal acyl chain length is C16, and aryl substituents are not tolerated. A variety of alkyl and acyl substituents on the cysteine amine were examined. All N-alkyl derivatives were inactive. In contradistinction, short-chain N-acyl analogues were found to be highly active, with a clear dependence on the chain length. A cysteine N-acetyl analogue was found to be the most potent (EC50: 1 nM), followed by the N-butyryl analogue. The N-acetyl analogue is human TLR2-specific, with its potency comparable to that of PAM2CS.

Salunke, Deepak B.; Shukla, Nikunj M.; Yoo, Euna; Crall, Breanna M.; Balakrishna, Rajalakshmi; Malladi, Subbalakshmi S.; David, Sunil A.

2012-01-01

319

Computer-aided study of the relationship between structure and antituberculosis activity of a series of isoniazid derivatives  

NASA Astrophysics Data System (ADS)

The Multiple Computer Automated Structure Evaluation (MultiCASE) program was used to analyze the relationship between the structure and antituberculous activity of a series of 136 hydrazides, most of them isoniazid related. The structural features revealed by this analysis are discussed. The most significant one seemed to be the distance between the pyridinic nitrogen and the terminal nitrogen of the hydrazido group. Given the affiliation of these two heteroatoms with a planar conjugated system, we suggest that Schiff base chemistry similar to that of vitamin B 6 may be involved in the mode of action of isoniazid and its related compounds. A mechanism of action of isoniazid is proposed and suggestions for the design of new isoniazid-type drugs are made.

Klopman, Gilles; Fercu, Dan; Jacob, Jason

1996-04-01

320

Estimation of relative binding free energy based on a free energy variational principle for quantitative structure activity relationship analyses  

NASA Astrophysics Data System (ADS)

In the present study, we try to estimate values of relative binding free energy of ligands to a protein based on a free energy variational principle. Results are used for quantitative structure activity relationship (QSAR) analyses. The aim of our study is to construct a procedure free from adjustable empirical parameters and expensive computational costs, and fast enough for use in QSAR. We apply our procedure to inhibitors of dehydrofolate reductase for which values of binding free energy have been studied extensively with both experimental and theoretical techniques. We demonstrate in this paper that we can obtain fairly good values when we can categorize ligands based on structural similarity or on the Log P values of substituents. The present results indicate that our procedure is valid and applicable to QSAR analyses for drug discovery when major differences in ligand structures can be regarded as small perturbations.

Shine, Yuichi; Kikuchi, Takeshi

2009-11-01

321

Development of novel pesticides based on phytoalexins: Part 2. Quantitative structure-activity relationships of 2-heteroaryl-4-chromanone derivatives.  

PubMed

Phytoalexins are low-molecular-weight chemicals that immune systems of plants produce and accumulate in response to infections, especially those of fungal origin. Although their content is not high in plants, yet they have shown unique fungicidal activity and played an important role in the defence system of plants. In searching for novel environmentally benign fungicides with high activity, the structures of flavanone derivatives, one of the most important phytoalexins groups, have been modified via bioisosteric substitution and a series of 2-heteroaryl-4-chromanones were designed and synthesized. They showed good fungicidal activities against rice blast disease, Pyricularia grisea (Sacc). Their IC50 values were tested in vitro and the relationship between structure and fungicidal activity was analyzed quantitatively using a Hansch-Fujita approach. The results showed that hydrophobicity was very important for fungicidal activity and there is apparently an optimum hydrophobic property for the molecules at a log Pow value of about 2.7. In addition, the results indicated that electronic effects played an important role in binding with the receptor and that the C=O group was probably a electron-accepting site. The quantitative structure-retention correlative equation of the title compounds was also established. PMID:12400447

Yang, Guangfu; Jiang, Xiaohua; Yang, Huazheng

2002-10-01

322

Lipolanthionine peptides act as inhibitors of TLR2-mediated IL-8 secretion. Synthesis and structure-activity relationships.  

PubMed

Lipoproteins from gram-positive and -negative bacteria, mycoplasma, and shorter synthetic lipopeptide analogues activate cells of the innate immune system via the Toll-like receptor TLR2/TLR1 or TLR2/TLR6 heterodimers. For this reason, these compounds constitute highly active adjuvants for vaccines either admixed or covalently linked. The lanthionine scaffold has structural similarity with the S-(2,3-dihydroxypropyl)cysteine core structure of the lipopeptides. Therefore, lanthionine-based lipopeptide amides were synthesized and probed for activity as potential TLR2 agonists or antagonists. A collection of analytically defined lipolanthionine peptide amides exhibited an inhibitory effect of the TLR2-mediated IL-8 secretion when applied in high molar excess to the agonistic synthetic lipopeptide Pam3Cys-Ser-(Lys)4-OH. Structure-activity relationships revealed the influence of the chirality of the two alpha-carbon atoms, the chain lengths of the attached fatty acids and fatty amines, and the oxidation level of the sulfur atom on the inhibitory activity of the lipolanthionine peptide amides. PMID:16509590

Seyberth, Tobias; Voss, Söhnke; Brock, Roland; Wiesmüller, Karl-Heinz; Jung, Günther

2006-03-01

323

Discovery and structure-activity relationship of 2-phenyl-oxazole-4-carboxamide derivatives as potent apoptosis inducers.  

PubMed

As a continuation of our efforts to discover novel apoptosis inducers as anticancer agents using a cell-based caspase HTS assay, 2-phenyl-oxazole-4-carboxamide derivatives were identified. The structure-activity relationships of this class of molecules were explored. Compound 1k, with EC(50) of 270 nM and GI(50) of 229 nM in human colorectal DLD-1 cells, was selected and demonstrated the ability to cleave PARP and displayed DNA laddering, the hallmarks of apoptosis. Compound 1k showed 63% tumor growth inhibition in human colorectal DLD-1 xenograft mouse model at 50 mpk, bid. PMID:16784854

Tai, Vincent W-F; Sperandio, David; Shelton, Emma J; Litvak, Joane; Pararajasingham, Keith; Cebon, Ben; Lohman, Julia; Eksterowicz, John; Kantak, Seema; Sabbatini, Peter; Brown, Cindy; Zeitz, Jennifer; Reed, Chris; Maske, Bill; Graupe, Doris; Estevez, Alberto; Oeh, Jason; Wong, Darren; Ni, Yong; Sprengeler, Paul; Yee, Robert; Magill, Catherine; Neri, Anthony; Cai, Sui Xiong; Drewe, John; Qiu, Ling; Herich, John; Tseng, Ben; Kasibhatla, Shailaja; Spencer, Jeffrey R

2006-06-19

324

Cardiovascular effects of gamma-MSH/ACTH-like peptides: structure-activity relationship.  

PubMed

Intravenous administration of gamma2-melanocyte-stimulating hormone (gamma2-MSH) to conscious rats causes a dose-dependent increase in blood pressure and heart rate, while the structurally related peptide adrenocorticotropic hormone-(4-10) (ACTH-(4-10)) is 5-10 times less potent in this respect. This prompted us to investigate which amino acid sequence is determinant for the cardiovascular selectivity of peptides of the gamma-MSH family. Lys-gamma2-MSH, most likely the endogenously occurring gamma-MSH analog, was as potent as gamma2-MSH in inducing increases in blood pressure and heart rate. Removal of C-terminal amino acids resulted in gamma-MSH-fragments which were devoid of cardiovascular activities. Removal of amino acids from the N-terminal side of gamma2-MSH resulted in fragments which were less potent, but had an intrinsic activity not different from that of gamma-MSH. Surprisingly, gamma-MSH-(6-12) was more potent than gamma2-MSH. The shortest fragment which displayed pressor and tachycardiac responses was the MSH 'core', His-Phe-Arg-Trp (= gamma-MSH-(5-8)), which is identical to ACTH-(6-9). This was corroborated by testing fragments of ACTH-(4-10). We conclude that the message essential for cardiovascular effects resides in the gamma-MSH-(5-8)/ACTH-(6-9) sequence. Proper C-terminal elongation is required for full expression of cardiovascular activity of gamma2-MSH, as the sequence of Asp9-Arg10-Phe11 appears to play an important role in establishing intrinsic activity. The amino acids N-terminal to the MSH 'core' sequence appear to be essential for the potency of the peptides. PMID:8750747

Van Bergen, P; Janssen, P M; Hoogerhout, P; De Wildt, D J; Versteeg, D H

1995-12-29

325

Anosognosia in mild cognitive impairment: Relationship to activation of cortical midline structures involved in self-appraisal  

PubMed Central

Awareness of cognitive dysfunction shown by individuals with Mild Cognitive Impairment (MCI), a condition conferring risk for Alzheimer’s disease (AD), is variable. Anosognosia, or unawareness of loss of function, is beginning to be recognized as an important clinical symptom of MCI. However, little is known about the brain substrates underlying this symptom. We hypothesized that MCI participants’ activation of cortical midline structures (CMS) during self-appraisal would covary with level of insight into cognitive difficulties (indexed by a discrepancy score between patient and informant ratings of cognitive decline in each MCI participant). To address this hypothesis, we first compared 16 MCI participants and 16 age-matched controls, examining brain regions showing conjoint or differential BOLD response during self-appraisal. Second, we used regression to investigate the relationship between awareness of deficit in MCI and BOLD activity during self-appraisal, controlling for extent of memory impairment. Between-group comparisons indicated that MCI participants show subtly attenuated CMS activity during self-appraisal. Regression analysis revealed a highly-significant relationship between BOLD response during self-appraisal and self-awareness of deficit in MCI. This finding highlights the level of anosognosia in MCI as an important predictor of response to self-appraisal in cortical midline structures, brain regions vulnerable to changes in early AD.

Ries, Michele L.; Jabbar, Britta M.; Schmitz, Taylor W.; Trivedi, Mehul A.; Gleason, Carey E.; Carlsson, Cynthia M.; Rowley, Howard A.; Asthana, Sanjay; Johnson, Sterling C.

2009-01-01

326

Structure-activity relationships of organic acid anhydrides as antigens in an animal model.  

PubMed

Relationships between chemical structure and immunogenicity have been studied in 13 dicarboxylic acid anhydrides. Guinea-pigs were immunized intradermally by a single dose of 0.3 M solutions of succinic anhydride (SA), maleic anhydride (MA), methylmaleic anhydride (MMA), cis-cyclohexane-1,2-dicarboxylic anhydride (cis-HHPA), trans-cyclohexane-1,2-dicarboxylic anhydride (trans-HHPA), 4-methylcyclohexane-1,2-dicarboxylic anhydride (MHHPA), cis-1,2,3,6-tetrahydrophthalic anhydride (THPA1236), cis-3,4,5,6-tetrahydrophthalic anhydride (THPA3456), cis-3-methylcyclohex-4-ene-1,2-dicarboxylic anhydride (MTHPA34), cis-4-methylcyclohex-4-ene-1,2-dicarboxylic anhydride (MTHPA44), phthalic anhydride (PA), 4-methylphthalic anhydride (MPA), and trimellitic anhydride (TMA) in olive oil. Specific IgE, IgG, IgG1, and IgG2 antibodies against guinea-pig serum albumin conjugates of the anhydrides were determined by passive cutaneous anaphylaxis (PCA) tests and enzyme-linked immunoabsorbant assay (ELISA). Specific IgG was significantly increased in all animals, except those immunized with THPA3456 and SA, which sensitized only 3/9 and 7/9 animals, respectively. Furthermore, the specific IgG values were very low in the SA group. The titers of specific IgG1 and IgG2 were increased in the IgG-positive animals. Specific IgE was positive in all animals immunized with MA, MHHPA, MTHPA (both isomers), and MPA, and in 6/9 and 5/9 guinea pigs immunized with TMA and MMA, respectively. The IgE titers were generally very low; PCA was negative after dilutions to 1:32, or less. The results indicate a considerable variation in the sensitizing potential between different organic acid anhydrides. The most marked general effect of the chemical structure on immunogenicity was the enhancement of antibody formation when a hydrogen atom in the anhydride was substituted with a methyl group. PMID:8545845

Welinder, H; Zhang, X; Gustavsson, C; Björk, B; Skerfving, S

1995-11-30

327

Anti-cancer efficacy of silybin derivatives -- a structure-activity relationship.  

PubMed

Silybin or silibinin, a flavonolignan isolated from Milk thistle seeds, is one of the popular dietary supplements and has been extensively studied for its antioxidant, hepatoprotective and anti-cancer properties. We have envisioned that potency of silybin could be further enhanced through suitable modification/s in its chemical structure. Accordingly, here, we synthesized and characterized a series of silybin derivatives namely 2,3-dehydrosilybin (DHS), 7-O-methylsilybin (7OM), 7-O-galloylsilybin (7OG), 7,23-disulphatesilybin (DSS), 7-O-palmitoylsilybin (7OP), and 23-O-palmitoylsilybin (23OP); and compared their anti-cancer efficacy using human bladder cancer HTB9, colon cancer HCT116 and prostate carcinoma PC3 cells. In all the 3 cell lines, DHS, 7OM and 7OG demonstrated better growth inhibitory effects and compared to silybin, while other silybin derivatives showed lesser or no efficacy. Next, we prepared the optical isomers (A and B) of silybin, DHS, 7OM and 7OG, and compared their anti-cancer efficacy. Isomers of these three silybin derivatives also showed better efficacy compared with respective silybin isomers, but in each, there was no clear cut silybin A versus B isomer activity preference. Further studies in HTB cells found that DHS, 7OM and 7OG exert better apoptotic activity than silibinin. Clonogenic assays in HTB9 cells further confirmed that both the racemic mixtures as well as pure optical isomers of DHS, 7OM and 7OG were more effective than silybin. Overall, these results clearly suggest that the anti-cancer efficacy of silybin could be significantly enhanced through structural modifications, and identify strong anti-cancer efficacy of silybin derivatives, namely DHS, 7OM, and 7OG, signifying that their efficacy and toxicity should be evaluated in relevant pre-clinical cancer models in rodents. PMID:23555889

Agarwal, Chapla; Wadhwa, Ritambhara; Deep, Gagan; Biedermann, David; Gažák, Radek; K?en, Vladimír; Agarwal, Rajesh

2013-03-28

328

QSAR of acridines, III. Structure-activity relationship for antitumour imidazoacridinones and intercorrelations between in vivo and in vitro tests.  

PubMed

A study on quantitative relationships between the biological activity and physicochemical properties of antitumour 5-alkylaminoimidazoacridinone derivatives was carried out. The activity was based on the results of several in vitro tests as well as experimental antileukaemic therapy. The capacity factor, log k', determined by the reverse-phase HPLC method, was a measure of lipophilic properties. UV and NMR spectra of the compounds were employed to describe electronic parameters. Values of steric descriptors were calculated as topological indexes. Results obtained by means of principal component analysis (PCA) allow us to group biological tests into two subsets: the lipophilicity-dependent and lipophilicity-independent test groups. The highest intercorrelation, R = 0.92, was shown between the optimal dose, pOD, determined in leukaemia P388-bearing mice and cytotoxicity expressed as pEC50 in leukaemia cells. The equation describing this relationship could be applied to predict the therapeutic doses of imidazoacridinone derivatives which would be effective in experimental antileukaemic therapy. The quantitative structure-activity relationship (QSAR) study showed that lipophilic properties significantly influence cytotoxicity, pEC50, and antileukaemic potency, pOD, only in the case of 8-hydroxy analogues of imidazoacridinones, whereas the activity of the remaining derivatives is very low and does not depend on lipophilicity. Electronic resonance properties seem to influence this specific impact of lipophilicity on the biological activity of 8-hydroxy derivatives. Hence, it may be possible to improve the antitumour activity of 8-hydroxyimidazoacridinones by obtaining more hydrophilic derivatives, up to the optimal value of the lipophilic parameter. PMID:8639249

Mazerska, Z; Augustin, E; Dziegielewski, J; Cho?ody, M W; Konopa, J

1996-01-01

329

Ecotoxicity quantitative structure-activity relationships for alcohol ethoxylate mixtures based on substance-specific toxicity predictions.  

PubMed

Traditionally, ecotoxicity quantitative structure-activity relationships (QSARs) for alcohol ethoxylate (AE) surfactants have been developed by assigning the measured ecotoxicity for commercial products to the average structures (alkyl chain length and ethoxylate chain length) of these materials. Acute Daphnia magna toxicity tests for binary mixtures indicate that mixtures are more toxic than the individual AE substances corresponding with their average structures (due to the nonlinear relation of toxicity with structure). Consequently, the ecotoxicity value (expressed as effects concentration) attributed to the average structures that are used to develop the existing QSARs is expected to be too low. A new QSAR technique for complex substances, which interprets the mixture toxicity with regard to the "ethoxymers" distribution (i.e., the individual AE components) rather than the average structure, was developed. This new technique was then applied to develop new AE ecotoxicity QSARs for invertebrates, fish, and mesocosms. Despite the higher complexity, the fit and accuracy of the new QSARs are at least as good as those for the existing QSARs based on the same data set. As expected from typical ethoxymer distributions of commercial AEs, the new QSAR generally predicts less toxicity than the QSARs based on average structure. PMID:16256196

Boeije, G M; Cano, M L; Marshall, S J; Belanger, S E; Van Compernolle, R; Dorn, P B; Gümbel, H; Toy, R; Wind, T

2005-10-26

330

Dendrotoxins: structure-activity relationships and effects on potassium ion channels.  

PubMed

Dendrotoxins are small proteins isolated from mamba (Dendroaspis) snakes. The original dendrotoxin was found in venom of the Eastern green mamba, Dendroaspis angusticeps, and related proteins were subsequently found in other mamba venoms. The dendrotoxins contain 57-60 amino acid residues cross-linked by three disulphide bridges, and they are homologous to Kunitz-type serine protease inhibitors, such as aprotinin (BPTI). The dendrotoxins have little or no anti-protease activity, but they block particular subtypes of voltage-dependent potassium channels of the Kv1 subfamily in neurones. Alpha-dendrotoxin from green mamba Dendroaspis angusticeps and toxin I from the black mamba Dendroaspis polylepis block cloned Kv1.1, Kv1.2 and Kv1.6 channels in the low nanomolar range; toxin K, also from the black mamba Dendroaspis polylepis, preferentially blocks Kv1.1 channels and is active at picomolar concentrations. Structural modifications and mutations to dendrotoxins have helped to define the molecular recognition properties of different types of K+ channels, although more work is needed to characterise the chemical features of the toxins that underlie their selectivity and potency at particular subtypes of channels. Dendrotoxins have been useful markers of subtypes of K+ channels in vivo, and dendrotoxins have become widely used as probes for studying the function of K+ channels in physiology and pathophysiology. With some pathological conditions being associated with voltage-gated K+ channels, analogues of dendrotoxins might have therapeutic potential. PMID:15579000

Harvey, A L; Robertson, B

2004-12-01

331

Structure-transfection activity relationships in a series of novel cationic lipids with heterocyclic head-groups.  

PubMed

Cationic liposomes are promising candidates for the delivery of various therapeutic nucleic acids. Here, we report a convenient synthesis of carbamate-type cationic lipids with various hydrophobic domains (tetradecanol, dialkylglycerol, cholesterol) and positively charged head-groups (pyridinium, N-methylimidazolium, N-methylmorpholinium) and data on the structure-transfection activity relationships. It was found that single-chain lipids possess high surface activity, which correlates with high cytotoxicity due to their ability to disrupt the cellular membrane by combined hydrophobic and electrostatic interactions. Liposomes containing these lipids also display high cytotoxicity with respect to all cell lines. Irrespective of chemical structures, all cationic lipids form liposomes with similar sizes and surface potentials. The characteristics of complexes composed of cationic liposomes and nucleic acids depend mostly on the type of nucleic acid and P/N ratios. In the case of oligodeoxyribonucleotide delivery, the transfection activity depends on the type of cationic head-group regardless of the type of hydrophobic domain: all types of cationic liposomes mediate efficient oligonucleotide transfer into 80-90% of the eukaryotic cells, and liposomes based on lipids with N-methylmorpholinium cationic head-group display the highest transfection activity. In the case of plasmid DNA and siRNA, the type of hydrophobic domain determines the transfection activity: liposomes composed of cholesterol-based lipids were the most efficient in DNA transfer, while liposomes containing glycerol-based lipids exhibited reasonable activity in siRNA delivery under serum-free conditions. PMID:24057052

Ivanova, Ekaterina A; Maslov, Mikhail A; Kabilova, Tatyana O; Puchkov, Pavel A; Alekseeva, Anna S; Boldyrev, Ivan A; Vlassov, Valentin V; Serebrennikova, Galina A; Morozova, Nina G; Zenkova, Marina A

2013-10-01

332

Structure-Activity Relationships in Predictive Toxicology. A Report of the CAAT Technical Workshop. Held in Baltimore, Maryland on June 21-22, 1990.  

National Technical Information Service (NTIS)

The Workshop on Structure-Activity Relationships in Predictive Toxicology conducted at the Johns Hopkins University School of Hygiene and Public Health was the third in the series of scientific workshops held under the auspices of the Johns Hopkins Center...

S. S. Sehnert

1990-01-01

333

Structure-activity relationship of alginate oligosaccharides in the induction of cytokine production from RAW264.7 cells.  

PubMed

Guluronate and mannuronate oligomers with various degree of polymerization were prepared from polyguluronate (PG) and polymannuronate (PM) with an alginate lyase from a Pseudoalteromonas sp., and their activities to induce cytokine secretion from mouse macrophage cell line RAW264.7 cells were examined. Enzymatically depolymerized unsaturated alginate oligomers induced tumor necrosis factor (TNF)-alpha secretion from RAW264.7 cells in a structure-depending manner, while the activities of saturated alginate oligomers prepared by acid hydrolysis were fairly low or only trace levels. These results suggest that unsaturated end-structure of alginate oligomers was important for the TNF-alpha-inducing activity. Among the unsaturated guluronate (G3-G9) and mannuronate (M3-M9) oligomers, G8 and M7 showed the most potent activity, respectively. Bio-Plex assay revealed that interleukin (IL)-1alpha, IL-1beta, and IL-6 secretion from RAW264.7 cells were also induced by unsaturated alginate oligomers with similar structure-activity relationship profiles as seen in TNF-alpha, and the most potent activities were observed with G8 and M7. These results suggest that G8 and M7 may have the most suitable molecular size or entire structural conformation as stimulant for cytokine secretion. Since antibodies to Toll-like receptor (TLR)2 and TLR4 effectively inhibited the G8- and M7-induced production of TNF-alpha, these alginate oligomers may stimulate innate immunity through the pattern recognition receptors on macrophages similar to microbial products. PMID:16055120

Iwamoto, Mami; Kurachi, Maki; Nakashima, Takuji; Kim, Daekyung; Yamaguchi, Kenichi; Oda, Tatsuya; Iwamoto, Yoshiko; Muramatsu, Tsuyoshi

2005-08-15

334

Avermectins and flea control: structure–activity relationships and the selection of selamectin for development as an endectocide for companion animals  

Microsoft Academic Search

Evaluation of a wide range of avermectin derivatives for flea activity in an in vitro feeding screen using the cat flea, Ctenocephalides felis, revealed a narrow structure–activity relationship (SAR) with activity surprisingly associated with monosaccharides and especially their C-5-oximes. We discovered commercially exploitable flea activity in a single compound, selamectin 33, which also possessed the necessary antiparasitic spectrum and margin

B. J. Banks; B. F. Bishop; N. A. Evans; S. P. Gibson; A. C. Goudie; K. A. F. Gration; M. S. Pacey; D. A. Perry; M. J. Witty

2000-01-01

335

Structure-activity relationships of 1'S-1'-acetoxychavicol acetate for inhibitory effect on NO production in lipopolysaccharide-activated mouse peritoneal macrophages.  

PubMed

1'S-1'-Acetoxychavicol acetate from the rhizomes of Alpinia galanga inhibited nitric oxide (NO) production in lipopolysaccharide-activated mouse peritoneal macrophages with an IC(50) value of 2.3 microM. To clarify the structure-activity relationship of 1'S-1'-acetoxychavicol acetate, various natural and synthetic phenylpropanoids and synthetic phenylbutanoids were examined, and the following structural requirements were clarified. (1) The para or ortho substitution of the acetoxyl and 1-acetoxypropenyl groups at the benzene ring was essential. (2) The S configuration of the 1'-acetoxyl group was preferable. (3) The presence of the 3-methoxyl group and disappearance of the 2'-3' double bond by hydrogenation reduced the activity. (4) The substitution of acetyl groups with propionyl or methyl groups reduced the activity. (5) Lengthening of the carbon chain between the 1'- and 2'-positions reduced the activity. PMID:15780639

Matsuda, Hisashi; Ando, Shin; Morikawa, Toshio; Kataoka, Shinya; Yoshikawa, Masayuki

2005-04-01

336

Structure Activity Relationships of Monocyte Chemoattractant Proteins in Complex with a Blocking Antibody  

SciTech Connect

Monocyte chemoattractant proteins (MCPs) are cytokines that direct immune cells bearing appropriate receptors to sites of inflammation or injury and are therefore attractive therapeutic targets for inhibitory molecules. 11K2 is a blocking mouse monoclonal antibody active against several human and murine MCPs. A 2.5 Angstroms structure of the Fab fragment of this antibody in complex with human MCP-1 has been solved. The Fab blocks CCR2 receptor binding to MCP-1 through an adjacent but distinct binding site. The orientation of the Fab indicates that a single MCP-1 dimer will bind two 11K2 antibodies. Several key residues on the antibody and on human MCPs were predicted to be involved in antibody selectivity. Mutational analysis of these residues confirms their involvement in the antibody- chemokine interaction. In addition to mutations that decreased or disrupted binding, one antibody mutation resulted in a 70-fold increase in affinity for human MCP-2. A key residue missing in human MCP-3, a chemokine not recognized by the antibody, was identified and engineering the preferred residue into the chemokine conferred binding to the antibody.

Reid,C.; Rushe, M.; Jarpe, M.; Van Vlijmen, H.; Dolinski, B.; Qian, F.; Cachero, T.; Cuervo, H.; Yanachkova, M.; et al.

2006-01-01

337

Mammary carcinogen-protein binding potentials: novel and biologically relevant structure-activity relationship model descriptors.  

PubMed

Previously, SAR models for carcinogenesis used descriptors that are essentially chemical descriptors. Herein we report the development of models with the cat-SAR expert system using biological descriptors (i.e., ligand-receptor interactions) rat mammary carcinogens. These new descriptors are derived from the virtual screening for ligand-receptor interactions of carcinogens, non-carcinogens, and mammary carcinogens to a set of 5494 target proteins. Leave-one-out validations of the ligand mammary carcinogen-non-carcinogen model had a concordance between experimental and predicted results of 71%, and the mammary carcinogen-non-mammary carcinogen model was 72% concordant. The development of a hybrid fragment-ligand model improved the concordances to 85 and 83%, respectively. In a separate external validation exercise, hybrid fragment-ligand models had concordances of 81 and 76%. Analyses of example rat mammary carcinogens including the food mutagen and oestrogenic compound PhIP, the herbicide atrazine, and the drug indomethacin; the ligand model identified a number of proteins associated with each compound that had previously been referenced in Medline in conjunction with the test chemical and separately with association to breast cancer. This new modelling approach can enhance model predictivity and help bridge the gap between chemical structure and carcinogenic activity by descriptors that are related to biological targets. PMID:20818582

Cunningham, A R; Qamar, S; Carrasquer, C A; Holt, P A; Maguire, J M; Cunningham, S L; Trent, J O

2010-07-01

338

Synthesis, antimicrobial, antimycobacterial and structure-activity relationship of substituted pyrazolo-, isoxazolo-, pyrimido- and mercaptopyrimidocyclohepta[b]indoles.  

PubMed

A new class of heterocycles, specifically substituted pyrazolo-, isoxazolo- and pyrimidocyclohepta[b]indoles, has been prepared by condensation of substituted 7-(hydroxymethylene)-7,8,9,10-tetrahydrocyclohepta[b]indol-6(5H)-ones with hydrazine hydrate, hydroxylamine hydrochloride, phenylhydrazine, urea and thiourea, respectively. The structures of the compounds were established by IR, (1)H NMR, (13)C NMR, mass spectral analysis, X-ray diffraction, and the compounds have been screened for in vitro antimicrobial and antimycobacterial against Mycobacterium tuberculosis H37Rv (MTB). Among the compounds screened, five substances were found to have an MIC of 3.12 ?g/ml or greater against MTB. Structure-activity relationship (SAR) analyses and in silico drug relevant properties (HBD, HBA, PSA, c Log P, M.wt) confirmed that the compounds are potential lead compounds for future drug discovery studies. PMID:22119150

Yamuna, Ezhumalai; Kumar, R Ajay; Zeller, Matthias; Rajendra Prasad, Karnam Jayarampillai

2011-11-13

339

Structure-activity relationship of 9-methylstreptimidone, a compound that induces apoptosis selectively in adult T-cell leukemia cells.  

PubMed

We previously reported that 9-methylstreptimidone, a piperidine compound isolated from a culture filtrate of Streptomyces, induces apoptosis selectively in adult T-cell leukemia cells. It was screened for a compound that inhibits LPS-induced NF-kappaB and NO production in mouse macrophages. However, 9-methystreptimidone is poorly obtained from the producing microorganism and difficult to synthesize. Therefore, in the present research, we studied the structure-activity relationship to look for new selective inhibitors. We found that the structure of the unsaturated hydrophobic portion of 9-methylstreptimidone was essential for the inhibition of LPS-induced NO production. Among the 9-methylstreptimidone-related compounds tested, (+/-)-4,alpha-diepi-streptovitacin A inhibited NO production in macrophage-like cells as potently as 9-methylstreptimidone and without cellular toxicity. Moreover, this compound selectively induced apoptosis in adult T-cell leukemia MT-1 cells. PMID:23035360

Takeiri, Masatoshi; Ota, Eisuke; Nishiyama, Shigeru; Kiyota, Hiromasa; Umezawa, Kazuo

2012-01-01

340

Structure activity relationship of antioxidative property of flavonoids and inhibitory effect on matrix metalloproteinase activity in UVA-irradiated human dermal fibroblast  

Microsoft Academic Search

Collagenase, a matrix metalloproteinases (MMPs), is a key regulator in the photoaging process of skin due to the reactive\\u000a oxygen species generated after exposure to ultraviolet A (UVA). Flavonoid compounds have been demonstrated to possess antioxidant\\u000a properties, and could be useful in the prevention of photoaging. In this study, to investigate the structure-activity relationship\\u000a of flavonoid compounds on their antioxidant

Gwan-Sub Sim; Bum-Chun Lee; Ho Seung Cho; Jae Woong Lee; Jin-Hwa Kim; Dong-Hwan Lee; Jin-Hui Kim; Hyeong-Bae Pyo; Dong Cheul Moon; Yeo Pyo Yun; Jin Tae Hong

2007-01-01

341

Non-peptide corticotropin-releasing hormone antagonists: syntheses and structure-activity relationships of 2-anilinopyrimidines and -triazines.  

PubMed

Screening of our chemical library using a rat corticotropin-releasing hormone (CRH) receptor assay led to the discovery that 2-anilinopyrimidine 15-1 weakly displaced [125I]-0-Tyr-oCRH from rat frontal cortex homogenates when compared to the known peptide antagonist alpha-helical CRH(9-41) (Ki = 5700 nM vs 1 nM). Furthermore, 15-1 weakly inhibited CRH-stimulated adenylate cyclase activity in the same tissue, but it was less potent than alpha-helical CRH(9-41) (IC50 = 20 000 nM vs 250 nM). Systematic structure-activity relationship studies, using the cloned human CRH1 receptor assay, defined the pharmacophore for optimal binding to hCRH1 receptors. Several high-affinity 2-anilinopyrimidines and -triazines were discovered, some of which had superior pharmacokinetic profiles in the rat. This paper describes the structure-activity studies which improved hCRH1 receptor binding affinity and pharmacokinetic parameters in the rat. Compound 28-17 (mean hCRH1 Ki = 32 nM) had a significantly improved pharmacokinetic profile in the rat (19% oral bioavailability at 30 mg/kg) as well as in the dog (20% oral bioavailability at 5 mg/kg) relative to the early lead structures. PMID:10072679

Arvanitis, A G; Gilligan, P J; Chorvat, R J; Cheeseman, R S; Christos, T E; Bakthavatchalam, R; Beck, J P; Cocuzza, A J; Hobbs, F W; Wilde, R G; Arnold, C; Chidester, D; Curry, M; He, L; Hollis, A; Klaczkiewicz, J; Krenitsky, P J; Rescinito, J P; Scholfield, E; Culp, S; De Souza, E B; Fitzgerald, L; Grigoriadis, D; Tam, S W; Shen, H L

1999-03-11

342

Structure-Activity Relationship Studies for the Peptide Portion of the Bladder Epithelial Cell Antiproliferative Factor from Interstitial Cystitis Patients  

PubMed Central

We performed comprehensive structure–activity relationship (SAR) studies on the peptide portion of antiproliferative factor (APF), a sialylated frizzled-8 related glycopeptide that inhibits normal bladder epithelial and urothelial carcinoma cell proliferation. Glycopeptide derivatives were synthesized by solid-phase methods using standard Fmoc chemistry and purified by RP-HPLC; all intermediate and final products were verified by HPLC-MS and NMR analyses. Antiproliferative activity of each derivative was determined by inhibition of 3H-thymidine incorporation in primary normal human bladder epithelial cells. Structural components of the peptide segment of APF that proved to be important for biological activity included the presence of at least eight of the nine N-terminal amino acids, a negative charge in the C-terminal amino acid, a free amino group at the N-terminus, maintenance of a specific amino acid sequence in the C-terminal tail, and trans conformation for the peptide bonds. These data provide critical guidelines for optimization of structure in design of APF analogues as potential therapeutic agents.

Kaczmarek, Piotr; Keay, Susan K.; Tocci, Gillian M.; Koch, Kristopher R.; Zhang, Chen-Ou; Barchi, Joseph J.; Grkovic, David; Guo, Li; Michejda, Christopher J.

2009-01-01

343

Synthesis and structure-activity relationships of 2-amino-3-carboxy-4-phenylthiophenes as novel atypical protein kinase C inhibitors.  

PubMed

Recent evidence suggests atypical protein kinase C (aPKC) isoforms are required for both TNF- and VEGF-induced breakdown of the blood-retinal barrier (BRB) and endothelial permeability to 70kDa dextran or albumin. A chemical library screen revealed a series of novel small molecule phenylthiophene based inhibitors of aPKC isoforms that effectively block permeability in cell culture and in vivo. In an effort to further elucidate the structural requirements of this series of inhibitors, we detail in this study a structure-activity relationship (SAR) built on screening hit 1, which expands on our initial pharmacophore model. The biological activity of our analogues was evaluated in models of bona fide aPKC-dependent signaling including NF?B driven-gene transcription as a marker for an inflammatory response and VEGF/TNF-induced vascular endothelial permeability. The EC50 for the most efficacious inhibitors (6, 32) was in the low nanomolar range in these two cellular assays. Our study demonstrates the key structural elements that confer inhibitory activity and highlights the requirement for electron-donating moieties off the C-4 aryl moiety of the 2-amino-3-carboxy-4-phenylthiophene backbone. These studies suggest that this class has potential for further development into small molecule aPKC inhibitors with therapeutic efficacy in a host of diseases involving increased vascular permeability and inflammation. PMID:23566515

Titchenell, Paul M; Hollis Showalter, H D; Pons, Jean-François; Barber, Alistair J; Jin, Yafei; Antonetti, David A

2013-03-13

344

Multiobjective particle swarm optimization: automated identification of structure-activity relationship-informative compounds with favorable physicochemical property distributions.  

PubMed

The selection of active compounds for chemical optimization efforts typically requires the consideration of multiple properties beyond potency. Herein we introduce a multiobjective particle swarm optimization approach to automatically extract compound subsets from large data sets that reveal structure-activity relationship (SAR) information and display physicochemical property distributions that are indicative of favorable absorption, distribution, metabolism, and excretion (ADME) characteristics. The approach is based on Pareto optimization of multiple objectives and does not require subjective intervention. It is automated and can be easily modified. We have applied the method to screen 10 compound data sets of different composition and global SAR phenotypes. In five of these data sets, between one and more than hundred compound subsets were identified that represented discontinuous local SARs and had desirable property distributions. PMID:23039232

Namasivayam, Vigneshwaran; Bajorath, Jürgen

2012-10-18

345

Synthesis and structure-activity relationship of novel conformationally restricted analogues of serotonin as 5-HT6 receptor ligands.  

PubMed

5-Hydroxytryptamine 6 receptors (5-HT(6)R) are being perceived as the possible target for treatment of cognitive disorders as well as obesity. The present article deals with the design, synthesis, in vitro binding and structure-activity relationship of a novel series of tetracyclic tryptamines with the rigidized N-arylsulphonyl, N-arylcarbonyl and N-benzyl substituents as 5-HT(6) receptor ligands. The chiral sulphonyl derivatives 15a and 17a showed high affinity at 5-HT(6)R with the K(i) of 23.4 and 20.5?nM, respectively. The lead compound from the series 15a has acceptable ADME properties, adequate brain penetration and is active in animal models of cognition like Novel Object Recognition Task (NORT) and water maze. PMID:21774748

Nirogi, Ramakrishna V S; Kambhampati, Ramasastri; Kothmirkar, Prabhakar; Konda, Jagadishbabu; Bandyala, Thrinath Reddy; Gudla, Parandhama; Arepalli, Sobhanadri; Gangadasari, Narasimhareddy P; Shinde, Anil K; Deshpande, Amol D; Dwarampudi, Adireddy; Chindhe, Anil K; Dubey, Pramod Kumar

2011-07-21

346

Quadruplex-interactive agents as telomerase inhibitors: synthesis of porphyrins and structure-activity relationship for the inhibition of telomerase.  

PubMed

The cationic porphyrin 5,10,15,20-tetra-(N-methyl-4-pyridyl)porphyrin (TMPyP4) binds to quadruplex DNA and is thereby an inhibitor of human telomerase (Wheelhouse et al. J. Am. Chem. Soc. 1998, 120, 3261-3262). Herein the synthesis and telomerase-inhibiting activity of a wide range of analogues of TMPyP4 are reported, from which rules for a structure-activity relationship (SAR) have been discerned: (1) stacking interactions are critical for telomerase inhibition, (2) positively charged substituents are important but may be interchanged and combined with hydrogen-bonding groups, and (3) substitution is tolerated only on the meso positions of the porphyrin ring, and the bulk of the substituents should be matched to the width of the grooves in which they putatively lie. This SAR is consistent with a model presented for the complexation of TMPyP4 with human telomeric quadruplex DNA. PMID:11741471

Shi, D F; Wheelhouse, R T; Sun, D; Hurley, L H

2001-12-20

347

Synthesis and structure-activity relationships of novel THF 1?-methylcarbapenems  

Microsoft Academic Search

A series of twelve highly active aminomethyl-THF 1?-methylcarbapenems 3a-1 were synthesized. Of these, carbapenems 3a-f demonstrated a spectrum of antimicrobial activity comparable to those of imipenem and meropenem with the exception of only moderate anti-pseudomonal activity. Most importantly, they demonstrated moderate intrinsic oral activity against an E. coli infection in mice.

Yang-I Lin; Panayota Bitha; Subas M. Sakya; Timothy W. Strohmeyer; Zhong Li; Ving J. Lee; Stanley A. Lang; Youjun Yang; Niraja Bhachech; William J. Weiss; Peter J. Petersen; Nilda V. Jacobus; Karen Bush; Raymond T. Testa; Francis P. Tally

1997-01-01

348

Structure-Activity Relationship for the First-in-Class Clinical Steroid Sulfatase Inhibitor Irosustat (STX64, BN83495)  

PubMed Central

Structure–activity relationship studies were conducted on Irosustat (STX64, BN83495), the first steroid sulfatase (STS) inhibitor to enter diverse clinical trials for patients with advanced hormone-dependent cancer. The size of its aliphatic ring was expanded; its sulfamate group was N,N-dimethylated, relocated to another position and flanked by an adjacent methoxy group; and series of quinolin-2(1H)-one and quinoline derivatives of Irosustat were explored. The STS inhibitory activities of the synthesised compounds were assessed in a preparation of JEG-3 cells. Stepwise enlargement of the aliphatic ring from 7 to 11 members increases potency, although a further increase in ring size is detrimental. The best STS inhibitors in vitro had IC50 values between 0.015 and 0.025 nm. Other modifications made to Irosustat were found to either abolish or significantly weaken its activity. An azomethine adduct of Irosustat with N,N-dimethylformamide (DMF) was isolated, and crystal structures of Irosustat and this adduct were determined. Docking studies were conducted to explore the potential interactions between compounds and the active site of STS, and suggest a sulfamoyl group transfer to formylglycine 75 during the inactivation mechanism.

Woo, L W Lawrence; Ganeshapillai, Dharshini; Thomas, Mark P; Sutcliffe, Oliver B; Malini, Bindu; Mahon, Mary F; Purohit, Atul; Potter, Barry V L

2011-01-01

349

Drug structure-transport relationships  

PubMed Central

Malcolm Rowland has greatly facilitated an understanding of drug structure–pharmacokinetic relationships using a physiological perspective. His view points, covering a wide range of activities, have impacted on my own work and on my appreciation and understanding of our science. This overview summarises some of our parallel activities, beginning with Malcolm’s work on the pH control of amphetamine excretion, his work on the disposition of aspirin and on the application of clearance concepts in describing the disposition of lidocaine. Malcolm also spent a considerable amount of time developing principles that define solute structure and transport/pharmacokinetic relationships using in situ organ studies, which he then extended to involve the whole body. Together, we developed a physiological approach to studying hepatic clearance, introducing the convection–dispersion model in which there was a spread in blood transit times through the liver accompanied by permeation into hepatocytes and removal by metabolism or excretion into the bile. With a range of colleagues, we then further developed the model and applied it to various organs in the body. One of Malcolm’s special interests was in being able to apply this knowledge, together with an understanding of physiological differences in scaling up pharmacokinetics from animals to man. The description of his many other activities, such as the development of clearance concepts, application of pharmacokinetics to the clinical situation and using pharmacokinetics to develop new compounds and delivery systems, has been left to others.

2010-01-01

350

Novel 4-substituted phenyl-2,2?-bichalcophenes and aza-analogs as antibacterial agents: a structural activity relationship  

PubMed Central

Antibiotic resistance is a major health problem; therefore, new antibacterial agents will need to be continuously developed. A series of novel bichalcophenes has been tested and found to have antimicrobial activity against selected bacteria. Due to the promising antimicrobial effects of these 4-substituted phenyl bichalcophene derivatives, the study reported here was launched to examine the interaction between novel bichalcophenes and tetracycline. The minimum inhibitory concentration values for all bichalcophenes were between 8 and 64 ?M. Many of the bichalcophenes had synergistic activity that increased the inhibitory effect of tetracycline against bacterial growth, as indicated by the fractional inhibitory concentration index. The post-antibiotic effects of the novel bichalcophenes were determined. Many bichalcophenes were able to elongate the period required for bacteria to recover and grow after a brief exposure to tetracycline. Escherichia coli did not develop resistance to many bichalcophenes over a period of 7 days. A structural activity relationship could be characterized, as monocationic derivatives were more active than the corresponding mononitriles. The presence of a pyridyl group and/or furan ring reduced the activity, while the presence of a phenyl or thiophene ring enhanced the antibacterial activity. Our results suggest that bichalcophenes could be useful to elevate the shelf life of many antibiotics.

Hussin, Warda A; Ismail, Mohamed A; El-Sayed, Wael M

2013-01-01

351

Naturally occurring phenolic antibacterial compounds show effectiveness against oral bacteria by a quantitative structure-activity relationship study.  

PubMed

Natural and synthetic phenolic compounds were evaluated against oral bacteria. A quantitative structure-active relationship approach was applied to the germ-kill activity for a range of phenolic compounds. The lipophilicity and steric effects were found to be two key factors in determining germ-kill activity. The optimum lipophilicity, measured by the logarithm of the octanol/water partition coefficient, or log P, was found to be 5.5 for Fusobacterium nucleatum , a Gram-negative type of oral bacteria that causes bad breath. The optimum log P was found to be 7.9 for Streptococcus mutans , a Gram-positive type of oral bacteria that causes tooth decay. The steric effect of substituents ortho to the phenolic group was found to be critical in reducing antibacterial activity despite having increased lipid solubility approaching the optimum lipophilicity value. The antibacterial activity of phenolic compounds is likely exerted by multiple functions, primarily comes from its ability to act as a nonionic surface-active agent therefore disrupting the lipid-protein interface. PMID:19007234

Greenberg, Michael; Dodds, Michael; Tian, Minmin

2008-12-10

352

Substituted 4-(Thiazol-5-yl)-2-(phenylamino)pyrimidines Are Highly Active CDK9 Inhibitors: Synthesis, X-ray Crystal Structures, Structure-Activity Relationship, and Anticancer Activities  

PubMed Central

Cancer cells often have a high demand for antiapoptotic proteins in order to resist programmed cell death. CDK9 inhibition selectively targets survival proteins and reinstates apoptosis in cancer cells. We designed a series of 4-thiazol-2-anilinopyrimidine derivatives with functional groups attached to the C5-position of the pyrimidine or to the C4-thiazol moiety and investigated their effects on CDK9 potency and selectivity. One of the most selective compounds, 12u inhibits CDK9 with IC50 = 7 nM and shows over 80-fold selectivity for CDK9 versus CDK2. X-ray crystal structures of 12u bound to CDK9 and CDK2 provide insights into the binding modes. This work, together with crystal structures of selected inhibitors in complex with both enzymes described in a companion paper,34 provides a rationale for the observed SAR. 12u demonstrates potent anticancer activity against primary chronic lymphocytic leukemia cells with a therapeutic window 31- and 107-fold over those of normal B- and T-cells.

2013-01-01

353

Abscisic Acid StructureActivity Relationships in Barley Aleurone Layers and Protoplasts  

Microsoft Academic Search

Optically active forms of abscisic acid (ABA) and their oxygen- ated metabolites were tested for their biological activity by exam- ining the effects of the compounds on the reversal of gibberellic acid-induced a-amylase activity in barley (Hordeum dgare cv Himalaya) aleurone layers and the induction of gene expression in barley aleurone protoplasts transformed with a chimeric construct containing the promoter

Robert D. Hill; Jin-Hao Liu; Douglas Durnin; Nancy Lamb; Angela Shaw; Suzanne R. Abrams

354

[Anti-inflammatory activity of the bark of Khaya senegalensis (A Juss). Preliminary research of structure/activity relationship].  

PubMed

Some anti-inflammatory tests based on the carrageenan induced oedema rat paw method have been carried out with a freeze-dried aqueous extract and an etheropetrolic extract of Cailcedrat (Khaya senegalensis) barks. Then, a preliminary chemical study to find a relation structure/activity has been done from the etheropetrolic extract, by using various chromatography technicals. The achieved results have shown a decrease of the oedema by 14% when the aqueous extract is used at 1 g.kg-1, 21.5% and 62% with the etheropetrolic extract used at the respecive doses of 0.5 g.kg-1 and 1 g.kg-1. As for the chemical study, it allowed the separation of two compounds which probably take part in noticed activity and are supposed to be methyl angolensate and methyl hydroxyangolensate. PMID:10797978

Thioune, O; Pousset, J L; Lo, I

1999-01-01

355

Cytotoxic and antioxidant effects of methoxylated stilbene analogues on HepG2 hepatoma and Chang liver cells: Implications for structure activity relationship.  

PubMed

Stilbenes possess a variety of biological activities including chemopreventive activity. This study was conducted to evaluate the structural activity relationships of six methoxylated stilbene analogues with respect to their cytotoxic effects and antioxidant activities on HepG2 hepatoma and Chang liver cells. The cytotoxic and total antioxidant activities of six stilbene analogues were determined by MTT and Ferric Reducing Antioxidant Power (FRAP) assays, respectively. We found that the cis-methoxylated stilbene: (Z)-3,4,4'-trimethoxystilbene was the most potent and selective antiproliferative agent (IC?? 89 µM) in HepG2 cells. For the total antioxidant activity, compounds possessing hydroxyl groups at the 4' position namely (E)-3-methoxy-4'-hydroxystilbene, (E)-3,5-dimethoxy-4'-hydroxystilbene (pterostilbene), (E)-4-methoxy-4'-hydroxystilbene showed the highest antioxidant activity. Structure activity relationship studies of these compounds demonstrated that the cytotoxic effect and antioxidant activities of the tested compounds in this study were structurally dependent. PMID:20385705

Hasiah, A H; Ghazali, A R; Weber, J F F; Velu, S; Thomas, N F; Inayat Hussain, S H

2010-04-12

356

Kinetic studies and structure-activity relationships of bispyridinium oximes as reactivators of acetylcholinesterase inhibited by organophosphorus compounds.  

PubMed

The kinetics of the reactivation of acetylcholinesterase inhibited by isopropyl methylphosphonofluoridate was studied. The reactivators used include nine bispyridinium monooximes and three bispyridinium dioximes. The dissociation constant (Kd) and the rate constant (k2) of dephosphorylation of the complex formed from the organophosphorus acetylcholinesterase (OP-AChE) and the oxime were measured. The reactivation parameters obtained from the in vitro kinetic studies were used to elucidate the structure-activity relationships. The hydrophobic property of a nonoxime substituent at the 3-position on the pyridinium ring can exert a positive effect on their binding affinity to OP-AChE. However, the rate constants (k2) of the nucleophilic displacement of OP-AChE by oximes depend negatively on these physical and structural factors of the oximes. The correlations of the in vivo antidotal efficacy (ED50) of these bispyridinium oximes have been analyzed with their pharmacological properties, e.g., reactivation potency, antimuscarinic activities, and antinicotinic activities. However, no satisfactory correlations were observed. It may be concluded that the detoxication mechanism of poisoning by isopropyl methylphosphonofluoridate is different from those of pinacolyl methylphosphonofluoridate and paraoxon. PMID:3699334

Su, C T; Wang, P H; Liu, R F; Shih, J H; Ma, C; Lin, C H; Liu, C Y; Wu, M T

1986-04-01

357

Peroxisome induction potential and lipid-regulating activity in rats. Quantitative microscopy and chemical structure-activity relationships.  

PubMed Central

Structurally diverse lipid-regulating agents induce hepatomegaly, hepatic peroxisome proliferation, and hepatocarcinoma in rats by mechanisms not fully understood. Nevertheless the initial hepatic response is a prompt, florid proliferation of peroxisomes. In investigations reported here, changes in the rat hepatic peroxisome compartment were measured by quantitative microscopy to determine chemical structure requirements that relate to peroxisome proliferation and lipid regulation. Aryloxyalkanoic acids plus amide analogs, and thio, benzimidazole, phenylpiperazine, and oxazole derivatives induced peroxisome proliferation and generally decreased plasma triglyceride and total cholesterol levels. These compounds contain an acidic function or are readily metabolized to a chemical with an acidic function. Substitution of the acidic function with an adamantyloxy eliminated peroxisome proliferation and induced contrasting effects on lipid profile, increasing triglycerides and decreasing total cholesterol. A previously unreported, direct correlation emerged between peroxisome proliferation and plasma high-density lipoprotein-cholesterol levels. These effects could not be elicited separately, negating identification of functional groups that could be associated with either activity. Chemical structure and resulting peroxisome proliferation with changes in plasma lipoproteins are therefore closely interrelated in rats. Images Figure 1

McGuire, E. J.; Lucas, J. A.; Gray, R. H.; de la Iglesia, F. A.

1991-01-01

358

Rational quantitative structure-activity relationship (RQSAR) screen for PXR and CAR isoform-specific nuclear receptor ligands.  

PubMed

Constitutive androstane receptor (CAR) and pregnane X receptor (PXR) are closely related orphan nuclear receptor proteins that share several ligands and target overlapping sets of genes involved in homeostasis and all phases of drug metabolism. CAR and PXR are involved in the development of certain diseases, including diabetes, metabolic syndrome and obesity. Ligand screens for these receptors so far have typically focused on steroid hormone analogs with pharmacophore-based approaches, only to find relatively few new hits. Multiple CAR isoforms have been detected in human liver, with the most abundant being the constitutively active reference, CAR1, and the ligand-dependent isoform CAR3. It has been assumed that any compound that binds CAR1 should also activate CAR3, and so CAR3 can be used as a ligand-activated surrogate for CAR1 studies. The possibility of CAR3-specific ligands has not, so far, been addressed. To investigate the differences between CAR1, CAR3 and PXR, and to look for more CAR ligands that may be of use in quantitative structure-activity relationship (QSAR) studies, we performed a luciferase transactivation assay screen of 60 mostly non-steroid compounds. Known active compounds with different core chemistries were chosen as starting points and structural variants were rationally selected for screening. Distinct differences in agonist versus inverse agonist/antagonist effects were seen in 49 compounds that had some ligand effect on at least one receptor and 18 that had effects on all three receptors; eight were CAR1 ligands only, three were CAR3 only ligands and four affected PXR only. This work provides evidence for new CAR ligands, some of which have CAR3-specific effects, and provides observational data on CAR and PXR ligands with which to inform in silico strategies. Compounds that demonstrated unique activity on any one receptor are potentially valuable diagnostic tools for the investigation of in vivo molecular targets. PMID:20869355

Dring, Ann M; Anderson, Linnea E; Qamar, Saima; Stoner, Matthew A

2010-10-20

359

Design, synthesis, and structure-activity relationship studies of ATP analogues as DNA gyrase inhibitors.  

PubMed

We report herein the design and synthesis of ATP-analogues, namely 4-amino-pyrazolo[3,4-d]pyrimidines and 4-amino-pyrazolo[1,5-a][1,3,5]triazines, with DNA gyrase inhibitory activity. Among these series, some compounds exhibited promising antibacterial activity. PMID:10782694

Lübbers, T; Angehrn, P; Gmünder, H; Herzig, S; Kulhanek, J

2000-04-17

360

Synthesis and insight into the structure-activity relationships of chalcones as antimalarial agents.  

PubMed

Licochalcone A (I), isolated from the roots of Chinese licorice, is the most promising antimalarial compound reported so far. In continuation of our drug discovery program, we isolated two similar chalcones, medicagenin (II) and munchiwarin (III), from Crotalaria medicagenia , which exhibited antimalarial activity against Plasmodium falciparum . A library of 88 chalcones were synthesized and evaluated for their in vitro antimalarial activity. Among these, 67, 68, 74, 77, and 78 exhibited good in vitro antimalarial activity against P. falciparum strains 3D7 and K1 with low cytotoxicity. These chalcones also showed reduction in parasitemia and increased survival time of Swiss mice infected with Plasmodium yoelii (strain N-67). Pharmacokinetic studies indicated that low oral bioavailability due to poor ADME properties. Molecular docking studies revealed the binding orientation of these inhibitors in active sites of falcipain-2 (FP-2) enzyme. Compounds 67, 68, and 78 showed modest inhibitory activity against the major hemoglobin degrading cysteine protease FP-2. PMID:23270565

Tadigoppula, Narender; Korthikunta, Venkateswarlu; Gupta, Shweta; Kancharla, Papireddy; Khaliq, Tanvir; Soni, Awakash; Srivastava, Rajeev Kumar; Srivastava, Kumkum; Puri, Sunil Kumar; Raju, Kanumuri Siva Rama; Wahajuddin; Sijwali, Puran Singh; Kumar, Vikash; Mohammad, Imran Siddiqi

2012-12-27

361

Structure-microbicidal activity relationship of synthetic fragments derived from the antibacterial alpha-helix of human lactoferrin.  

PubMed

There is a need for new microbicidal agents with therapeutic potential due to antibiotic resistance in bacteria and fungi. In this study, the structure-microbicidal activity relationship of amino acid residues 14 to 31 (sequence 14-31) from the N-terminal end, corresponding to the antibacterial alpha-helix of human lactoferrin (LF), was investigated by downsizing, alanine scanning, and substitution of amino acids. Microbicidal analysis (99% killing) was performed by a microplate assay using Escherichia coli, Staphylococcus aureus, and Candida albicans as test organisms. Starting from the N-terminal end, downsizing of peptide sequence 14-31 showed that the peptide sequence 19-31 (KCFQWQRNMRKVR, HL9) was the optimal length for antimicrobial activity. Furthermore, HL9 bound to lipid A/lipopolysaccharide, as shown by neutralizing endotoxic activity in a Limulus assay. Alanine scanning of peptide sequence 20-31 showed that Cys20, Trp23, Arg28, Lys29, or Arg31 was important for expressing full killing activity, particularly against C. albicans. Substituting the neutral hydrophilic amino acids Gln24 and Asn26 for Lys and Ala (HLopt2), respectively, enhanced microbicidal activity significantly against all test organisms compared to the amino acids natural counterpart, also, in comparison with HL9, HLopt2 had more than 10-fold-stronger fungicidal activity. Furthermore, HLopt2 was less affected by metallic salts than HL9. The microbicidal activity of HLopt2 was slightly reduced only at pH 7.0, as tested in the pH range of 4.5 to 7.5. The results showed that the microbicidal activity of synthetic peptide sequences, based on the antimicrobial alpha-helix region of LF, can be significantly enhanced by optimizing the length and substitution of neutral amino acids at specific positions, thus suggesting a sequence lead with therapeutic potential. PMID:19917761

Håversen, L; Kondori, N; Baltzer, L; Hanson, L A; Dolphin, G T; Dunér, K; Mattsby-Baltzer, I

2009-11-16

362

Methanolysis of triterpenoid saponin from Ardisia gigantifolia stapf. and structure-activity relationship study against cancer cells.  

PubMed

Thirteen 13,28-epoxy triterpenoid saponins were isolated from Ardisia gigantifolia stapf. and one potential anti-tumor saponin was methanolysised by H2SO4 to afford four new compounds. The seventeen compounds were evaluated for their anti-proliferative activity on A549, HCT-8 and Bel-7402 cells. The structure-activity relationship analysis indicated that the incorporation of O group at C-16, l-rhamnose at R(5) and acetyl group at OH-6 of the d-glucose lead to a significant increase of the cytotoxic activity on A549 and HCT-8 but significant reduction of the cytotoxic activity on Bel-7402 cells. The synthesized saponins losing 13,28-epoxy and CHO at C-30, losed their cytotoxicities on A549 and HCT-8 cells, suggesting that the two moieties play an essential role for activity. 3?-O-?-l-rhamnopyranosyl-(1?3)-[?-d-xylopyranosyl-(1?2)]-?-d-glucopyranosyl-(1?4)-[?-d-glucopyranosyl-(1?2)]-?-l-arabinopyranoside-16?-hydroxy-13,28-epoxy-oleanane (2) showed better inhibitory activity to Bel-7402 (IC50 0.86?M) than that of 5-FU (IC50 8.30?M), which indicate that five saccharide and methyl moiety at C-30 are important for anti-proliferative activity. The activities of saponins 15>14, 17>16, suggested that the configuration of 28,30-epoxy is preferable to be 30(R) rather than 30(S) on Bel-7402 cells. Further molecular mechanism studies of saponins 1 and 2 were carried out on the cell cycle distribution of Bel-7402 cells. PMID:24095094

Mu, Li-Hua; Huang, Cui-Li; Zhou, Wen-Bin; Guo, Dai-Hong; Liu, Ping

2013-09-18

363

Conformation and charge distribution of bicyclic beta-lactams: structure-activity relationships.  

PubMed

The structures of 7-oxo-1-azabicyclo[3.2.0]heptane and its 4-oxa, 3-ethylene-4-oxa, and 3-ethylene-6-methyl-4-oxa derivatives, and of 8-oxo-1-azabicyclo[4.2.0]octane and its 5-oxa derivative, were studied by ab initio methods. Conformations were refined without constraints using the 4-21G and the 4-21G* basis sets, and energies and charge distributions were improved by single-point 6-31G*/4-21G* calculations. The results are are interpreted in terms of structural trends related to beta-lactamase inhibitor capability. PMID:1617153

Fernández, B; Carballeira, L; Ríos, M A

1992-01-01

364

Structure-activity relationships of C-17-substituted estratriene-3-O-sulfamates as anticancer agents.  

PubMed

The synthesis and antiproliferative activities of analogues of 2-substituted estradiol-3,17-O,O-bis-sulfamates (E2bisMATEs) are discussed. Modifications of the C-17 substituent confirm that an H-bond acceptor is essential for high activity; its optimal linkage to C-17 and the local environment in which it resides are defined. In the non-sulfamoylated series 17?-acyl substitution delivers 48b, the most potent compound identified to date. In the sulfamate series a number of permutations of linker and H-bond acceptor deliver excellent activity, with 55, 61, 65, 49a, and 49b proving especially promising. The in vivo potential of these compounds was explored in the NCI hollow fiber assay and also in a mouse Matrigel model of antiangiogenesis in which 49 and 55 show significant inhibitory activity. PMID:21604672

Jourdan, Fabrice; Leese, Mathew P; Dohle, Wolfgang; Ferrandis, Eric; Newman, Simon P; Chander, Surinder; Purohit, Atul; Potter, Barry V L

2011-06-09

365

Gedunin, a Novel Hsp90 Inhibitor: Semisynthesis of Derivatives and Preliminary Structure-Activity Relationships  

PubMed Central

Gedunin (1), a tetranortriterpenoid isolated from the Indian neem tree (Azadirachta indica), was recently shown to manifest anticancer activity via inhibition of the 90 kDa heat shock protein (Hsp90) folding machinery and to induce the degradation of Hsp90-dependent client proteins similar to other Hsp90 inhibitors. The mechanism of action by which gedunin induces client protein degradation remains undetermined, however, prior studies have demonstrated that it does not bind competitively versus ATP. In an effort to further probe the mechanism of action, 19 semisynthetic derivatives of gedunin were prepared and their antiproliferative activity against MCF-7 and SkBr3 breast cancer cells determined. Although no compound was found to exhibit antiproliferative activity more effective than the natural product, functionalities critical for antiproliferative activity have been identified.

Brandt, Gary E. L.; Schmidt, Matthew D.; Prisinzano, Thomas E.; Blagg, Brian S. J.

2010-01-01

366

Evaluation and structure-activity relationship study of acute toxicity of naphthoquinones to Photobacterium phosphoreum, Photobacterium T3B.  

PubMed

The acute toxicities of five naphthoquinone compounds to Photobacterium phosphoreum were determined. We evaluated the mechanism of toxicity using the structure-activity relationship technique. The results showed that some factors, including the species of substituents, shape/size of molecule and oil-water partition coefficient (log P) played the important roles in the interaction between the naphthoquinones and the target. Among of these, the toxicities of Atovaquone and Buparvaquone were lower than the other naphthoquinones we tested because of the alkyl-substitution with the bigger volume and strong hydrophobicity. Conversely, Menadione had the highest toxicity because of the appropriate log P and shape/size of molecule resulting in the easier interaction with the target. PMID:20640400

Ding, Feng; Guo, Jing; Li, Zhen; Li, Li Ying; Zhang, Jin Yang; Zhang, Jin Hua; Lian, Jie; Song, Wen Hua; Zhu, Lin

2010-07-17

367

Synthesis and structure-activity relationship studies of 3-substituted indolin-2-ones as effective neuroprotective agents.  

PubMed

Neurodegenerative diseases are a major health problem particularly among the elderly. Drugs to prevent or slow down the death of neurons are urgently needed but are currently unavailable. We previously reported that the c-Raf inhibitor, GW5074 {5-iodo-3-[(3',5'-dibromo-4'-hydroxyphenyl) methylene]-2-indolinone}, is protective in tissue culture and in vivo paradigms of neurodegeneration. However, at doses slightly higher than those at which it is protective, GW5074 displays toxicity when tested in neuronal cultures. We report herein the synthesis, biological evaluation, and structure-activity relationship (SAR) studies of novel 3-substituted indolin-2-one compounds that are highly neuroprotective but lack the toxicity of GW5074. Of the 45 analogs tested in this study, compounds 7, 37, 39, and 45 were found to be the most potent neuroprotective and thus represent promising lead compounds for preclinical development for the treatment of neurodegenerative disorders. PMID:18957634

Balderamos, Michael; Ankati, Haribabu; Akubathini, Shashidhar Kumar; Patel, Anish V; Kamila, Sukanta; Mukherjee, Chandrani; Wang, Lulu; Biehl, Edward R; D'Mello, Santosh R

2008-11-01

368

Structure-activity relationship studies of sulfonylpiperazine analogs as novel negative allosteric modulators of human neuronal nicotinic receptors  

PubMed Central

Neuronal nicotinic receptors have been implicated in several diseases and disorders such as: autism, Alzheimer’s disease, Parkinson’s disease, epilepsy, and various forms of addiction. To understand the role of nicotinic receptors in these conditions, it would be beneficial to have selective molecules that target specific nicotinic receptors in vitro and in vivo. Our laboratory has previously identified novel negative allosteric modulators of human ?4?2 (H?4?2) and human ?3?4 (H?3?4) nicotinic receptors. In the following studies, the effects of novel sulfonylpiperazine analogs that act as negative allosteric modulators on both H?4?2 nAChRs and H?3?4 nAChRs were investigated. This work, through structure-activity relationship (SAR) studies, describes the chemical features of these molecules that are important for both potency and selectivity on H?4?2 nAChRs.

Henderson, Brandon J.; Carper, Daniel J.; Gonzaez-Cestari, Tatiana F.; Yi, Bitna; Mahasenan, Kiran; Pavlovicz, Ryan E.; Dalefield, Martin L.; Coleman, Robert S.; Li, Chenglong; McKay, Dennis B.

2011-01-01

369

Design, synthesis and structure?activity relationships of novel biarylamine-based Met kinase inhibitors  

SciTech Connect

Biarylamine-based inhibitors of Met kinase have been identified. Lead compounds demonstrate nanomolar potency in Met kinase biochemical assays and significant activity in the Met-driven GTL-16 human gastric carcinoma cell line. X-ray crystallography revealed that these compounds adopt a bioactive conformation, in the kinase domain, consistent with that previously seen with 2-pyridone-based Met kinase inhibitors. Compound 9b demonstrated potent in vivo antitumor activity in the GTL-16 human tumor xenograft model.

Williams, David K.; Chen, Xiao-Tao; Tarby, Christine; Kaltenbach, Robert; Cai, Zhen-Wei; Tokarski, John S.; An, Yongmi; Sack, John S.; Wautlet, Barri; Gullo-Brown, Johnni; Henley, Benjamin J.; Jeyaseelan, Robert; Kellar, Kristen; Manne, Veeraswamy; Trainor, George L.; Lombardo, Louis J.; Fargnoli, Joseph; Borzilleri, Robert M. (BMS)

2010-09-03

370

Macrobenthos community structure and trophic relationships within active and inactive Pacific hydrothermal sediments  

Microsoft Academic Search

Hydrothermal fluids passing through sediments create a habitat hypothesized to influence the community structure of infaunal macrobenthos. Here we characterize the density, biomass, species composition, diversity, distributions, lifestyle, and nutritional sources of macroinfauna in hydrothermal sediments in NE and SW Pacific settings, and draw comparisons in search of faunal attributes characteristic of this habitat. There is increasing likelihood that seafloor

Lisa A. Levin; Guillermo F. Mendoza; Talina Konotchick; Raymond Lee

2009-01-01

371

Computational Structure-Activity Relationship Analysis of Non-peptide Inducers of Macrophage Tumor Necrosis Factor-? Production  

PubMed Central

Previously, we screened a series of arylcarboxylic acid hydrazide derivatives for their ability to induce macrophage tumor necrosis factor ? (TNF-?) production and identified 16 such compounds. In the present study, we evaluated 23 additional arylcarboxylic acid hydrazides and found that seven of these compounds also induced macrophage TNF-? production, representing novel compounds with this activity. The total set of active compounds was then used for computational structure–activity relationship (SAR) analysis to further optimize lead molecules. A sequence of 1) linear discriminant analysis, 2) classification tree analysis with linear combination, and 3) univariate splits based on atom pair descriptors led to the derivation of SAR rule-based algorithms with fittng accuracy of 96.5, 91.9, and 84.9%, respectively. The SAR rules obtained from classification tree analysis with univariate splits, which was based on three atom pair descriptors only, revealed that the main factors influencing agonist activity of arylcarboxylic acid hydrazide derivatives were the presence of a methyl or trifluoromethyl group in the benzene ring attached to the furan moiety, an alkoxy group in the aromatic ring near the methylenehydrazide linker, and two or more halogen atoms (chlorine or bromine) on one side of the dumbbell-shaped hydrazide molecule opposed by an aromatic moiety on the opposite side of the molecule. Thus, these rules represent a relatively simple classification approach for de novo design of small molecule inducers of macrophage TNF-? production.

Khlebnikov, Andrei I.; Schepetkin, Igor A.; Kirpotina, Liliya N.; Quinn, Mark T.

2008-01-01

372

Structure-activity relationships of adenine and deazaadenine derivatives as ligands for adenine receptors, a new purinergic receptor family.  

PubMed

Adenine derivatives bearing substituents in the 2-, N(6)-, 7-, 8-, and/or 9-position and a series of deazapurines were synthesized and investigated in [(3)H]adenine binding studies at the adenine receptor in rat brain cortical membrane preparations (rAde1R). Steep structure-activity relationships were observed. Substitution in the 8-position (amino, dimethylamino, piperidinyl, piperazinyl) or in the 9-position (2-morpholinoethyl) with basic residues or introduction of polar substituents at the 6-amino function (hydroxy, amino, acetyl) represented the best modifications. Functional evaluation of selected adenine derivatives in adenylate cyclase assays at 1321N1 astrocytoma cells stably expressing the rAde1R showed that all compounds investigated were agonists or partial agonists. A subset of compounds was additionally investigated in binding studies at human embryonic kidney (HEK293) cells, which also express a high-affinity adenine binding site. Structure-affinity relationships at the human cell line were similar to those at the rAde1R, but not identical. In particular, N(6)-acetyladenine (25, K(i) rat: 2.85 microM; K(i) human: 0.515 microM) and 8-aminoadenine (33, K(i) rat: 6.51 microM; K(i) human: 0.0341 microM) were much more potent at the human as compared to the rat binding site. The new AdeR ligands may serve as lead structures and contribute to the elucidation of the functions of the adenine receptor family. PMID:19731917

Borrmann, Thomas; Abdelrahman, Aliaa; Volpini, Rosaria; Lambertucci, Catia; Alksnis, Edgars; Gorzalka, Simone; Knospe, Melanie; Schiedel, Anke C; Cristalli, Gloria; Müller, Christa E

2009-10-01

373

Structure-activity relationships for alpha calcitonin gene-related peptide.  

PubMed

Calcitonin gene-related peptide (CGRP) is a member of the calcitonin family of peptides. It is a widely distributed neuropeptide implicated in conditions such as neurogenic inflammation. With other members of the calcitonin family, it shares an N-terminal disulphide-bonded ring which is essential for biological activity, an area of potential alpha helix, and a C-terminal amide. CGRP binds to the calcitonin receptor-like receptor (CLR) in complex with receptor activity modifying protein 1 (RAMP1), a member of the family B (or Secretin-like) G protein-coupled receptors (GPCRs). It can also activate other CLR or calcitonin-receptor/RAMP complexes. This 37 amino acid peptide comprises the N-terminal ring that is required for receptor activation (residues 1-7); an alpha helix (residues 8-18), a region incorporating a beta bend (residues 19-26) and the C-terminal portion (residues 27-37), that is characterised by bends between residues 28-30 and 33-34. A few residues have been identified that seem to make major contributions to receptor binding and activation, with a larger number contributing either to minor interactions (which collectively may be significant) or, to maintaining the conformation of the bound peptide. It is not clear if CGRP follows the pattern of other family B GPCRs in binding largely as an alpha helix. PMID:23186257

Watkins, Harriet A; Rathbone, Dan L; Barwell, James; Hay, Debbie L; Poyner, David R

2012-11-27

374

Chemical derivatization as a strategy to study structure-activity relationships of glycosaminoglycans.  

PubMed

Sulfated glycosaminoglycans (GAGs) are amenable to a number of chemical modifications that modulate their biological activity. N-sulfate groups can be exposed and N-acylated (usually N-acetylated), specific O-sulfate groups can be removed, and free hydroxyl groups (either preexisting in the original GAG or exposed by desulfation) can be sulfated. Heparin/heparan sulfate, chondroitin sulfate, and dermatan sulfate have been variously desulfated or sulfated to afford novel GAGs with protein binding and associated biological properties different from those of the original GAGs. Regiospecific sulfation of N-acetyl heparosan ( E. coli K5 polysaccharide) afforded a number of derivatives, some endowed with antithrombotic activity and others with antimetastatic properties. Most of the activities could be correlated with typical sulfation patterns along each GAG backbone. Glycol splitting of nonsulfated glucuronic residues (including a critical residue in the pentasaccharide sequence of the active site for antithrombin) leads to substantial loss of anticoagulant activity of heparin. Partial removal of sulfate groups at position 2 of iduronic acid residues followed by glycol splitting of all nonsulfated uronic acid residues afforded nonanticoagulant, antiangiogenic heparins. PMID:12244480

Casu, Benito; Naggi, Annamaria; Torri, Giangiacomo

2002-08-01

375

Structure-activity relationships in nucleotide oligomerization domain 1 (Nod1) agonistic ?-glutamyldiaminopimelic acid derivatives.  

PubMed

N-acyl-?-glutamyldiaminopimelic acid is a prototype ligand for Nod1. We report a detailed SAR of C(12)-?-D-Glu-DAP. Analogues with glutaric or ?-aminobutyric acid replacing the glutamic acid show greatly attenuated Nod1-agonistic activity. Substitution of the meso-diaminopimelic (DAP) acid component with monoaminopimelic acid, L- or D-lysine, or cadaverine also results in reduced activity. The free amine on DAP is crucial. However, the N-acyl group on the D-glutamyl residue can be substituted with N-alkyl groups with full preservation of activity. The free carboxylates on the DAP and Glu components can also be esterified, resulting in more lipophilic but active analogues. Transcriptomal profiling showed a dominant up-regulation of IL-19, IL-20, IL-22, and IL-24, which may explain the pronounced Th2-polarizing activity of these compounds and also implicate cell signaling mediated by TREM-1. These results may explain the hitherto unknown mechanism of synergy between Nod1 and TLR agonists and are likely to be useful in designing vaccine adjuvants. PMID:21299227

Agnihotri, Geetanjali; Ukani, Rehman; Malladi, Subbalakshmi S; Warshakoon, Hemamali J; Balakrishna, Rajalakshmi; Wang, Xinkun; David, Sunil A

2011-02-07

376

Structure-activity relationships of analogs of pentamidine against Plasmodium falciparum and Leishmania mexicana amazonensis.  

PubMed Central

The antiprotozoal compound 1,5-di(4-amidinophenoxy)pentane (pentamidine) and 36 of its analogs were screened for in vitro activity against Leishmania mexicana amazonensis clone 669 C4S (MHOM/BR/73/M2269) and Plasmodium falciparum clones W2 (Indochina III/CDC) and D6 (Sierra Leone I/CDC). Pentamidine and each of the analogs tested exhibited activity in vitro against L. m. amazonensis and P. falciparum. The pentamidine analogs were more effective against the P. falciparum clones than against L. m. amazonensis. P. falciparum was extremely susceptible to these compounds, with 50% inhibitory concentrations as low as 0.03 microM. While none of the analogs exhibited marked improvement in antileishmanial activity compared with pentamidine, 12 of the pentamidine analogs showed activity approximately equal to or greater than that of the parent compound. From the promising activity exhibited by the pentamidine analogs in this in vitro study and their potential for reduced toxicity relative to the parent drug, pentamidine-related compounds hold promise as new agents for the treatment of protozoal infections.

Bell, C A; Hall, J E; Kyle, D E; Grogl, M; Ohemeng, K A; Allen, M A; Tidwell, R R

1990-01-01

377

Structure-activity relationship of 15 different Mn-salen derivatives against free radicals.  

PubMed

Increased levels of reactive oxygen species (ROS) play a vital role in the pathogenesis of various diseases. Thus, antioxidants would play pivotal roles in the therapy of ROS-induced diseases. Regarding this fact, in the present study, we compared the relative scavenging potency and cytoprotective effects of 15 Mn-salen complexes (EUKs: eukarion antioxidant compounds), having different substituted groups, against induced free radicals (O(2)(?-), H(2)O(2), (?)OH, and ABTS(?+)) and protein carbonylation (PCO) in vitro as well as H(2)O(2)-induced damages and lipofuscin production in cellular systems. The results revealed that all Mn-salen complexes had considerable effects on O(2)(?-), H(2)O(2), and (?)OH scavenging, relative to common antioxidants, in a concentration-dependent manner. Further, our data demonstrated that the nature and position of different substitutions on the salen ring had significant effects on scavenging activity, PCO formation, as well as suppression of cytotoxicity and apoptosis induced in cells by H(2)O(2). Among studied complexes, EUK-15 and -123 showed the most catalase and superoxide dismutase activities, whereas their (?)OH-scavenging activities were very weak. The cytoprotective effects of the salens, mainly EUK-15 and -123, were also associated with a significant reduction in the extent of intracellular lipofuscin pigments. Evaluation of the 15 salen derivatives clearly indicated these compounds possess ROS-scavenging activity and this activity is potentiated by the presence of para and ortho alkoxy groups. PMID:22263563

Meftah, Sakineh; Sajadimajd, Soraya; Yazdanparast, Razieh

2012-01-21

378

Relationship between structure and antiplaque and antimicrobial activities for a series of bispyridines.  

PubMed Central

A series of bispyridines were examined for their bactericidal activities against in vitro, preformed, pure-culture plaques of selected oral plaque-forming bacteria. The antimicrobial activities of these agents were examined in relation to their molecular configurations. These studies demonstrated that the length of the interpyridine polymethylene group bridge and the length of the alkyl side chain were important determinants of antiplaque and antimicrobial efficacy. The most potent compounds of the bispyridine series were studied to determine the minimal conditions (concentration, duration, and frequency) of treatment required for likely clinical efficacy.

Slee, A M; O'Connor, J R; Bailey, D M

1983-01-01

379

Structure-activity relationship for quaternary ammonium compounds hybridized with poly(methyl methacrylate).  

PubMed

Hybrid films from poly (methylmethacrylate) (PMMA) and dioctadecyldimethylammonium bromide (DODAB), cetyltrimethylammonium bromide (CTAB), or tetrapropylammonium bromide (TPAB) were characterized by determination of wettability, ellipsometry, atomic force microscopy, active compounds diffusion to water, X-ray photoelectron spectroscopy (XPS) with determination of atomic composition on the films surface, and biocidal activity against Pseudomonas aeruginosa or Staphylococcus aureus. QAC mobility in the films increased from DODAB to CTAB to TPAB. Diffusion and optimal hydrophobic-hydrophilic balance imparted the highest bioactivity to CTAB. DODAB sustained immobilization at the film surface killed bacteria upon contact. TPAB ability to diffuse was useless because of its unfavorable hydrophobic-hydrophilic balance for bioactivity. PMID:21591705

Melo, Leticia D; Palombo, Renata R; Petri, Denise F S; Bruns, Michael; Pereira, Edla M A; Carmona-Ribeiro, Ana M

2011-05-27

380

Structure-activity relationships for skin sensitization: recent improvements to Derek for Windows.  

PubMed

Derek for Windows (DfW) is a knowledge-based expert system that predicts the toxicity of a chemical from its structure. Its predictions are based in part on alerts that describe structural features or toxicophores associated with toxicity. Recently, improvements have been made to skin sensitization alerts within the DfW knowledge base in collaboration with Unilever. These include modifications to the alerts describing the skin sensitization potential of aldehydes, 1,2-diketones, and isothiazolinones and consist of enhancements to the toxicophore definition, the mechanistic classification, and the extent of supporting evidence provided. The outcomes from this collaboration demonstrate the importance of updating and refining computer models for the prediction of skin sensitization as new information from experimental and theoretical studies becomes available. PMID:17101009

Langton, Kate; Patlewicz, Grace Y; Long, Anthony; Marchant, Carol A; Basketter, David A

2006-12-01

381

Structure-activity relationships in hydroxy-2,3-diarylxanthone antioxidants. Fast kinetics spectroscopy as a tool to evaluate the potential for antioxidant activity in biological systems.  

PubMed

A structure-activity relationship has been established for eight hydroxy-2,3-diarylxanthones (XH) bearing hydroxy groups on the two aryl rings. One-electron oxidation by superoxide radical-anions (?O(2)(-)) and ?Trp radicals as well as reaction with ?CCl(3)O(2) and ?CHCl(2)O(2) radicals demonstrates that two OH groups are required for efficient antioxidant reactivity in cetyltrimethylammonium bromide micelles. Hydroxy groups at the meta and para positions on either of the two phenyl rings confer enhanced reactivity, but XH bearing an OH at the para position of either phenyl ring is unreactive. While oxidation is favoured by OH in both meta and para positions of 2-aryl xanthone substituents, addition of a third and/or fourth OH enhances electron-donating capacity. In Cu(2+)-induced lipid peroxidation of human LDL, the lag period preceding the commencement of lipid peroxidation in the presence of XH bearing OH at meta and para positions on the 3-phenyl ring is extended to twice that observed with a comparable concentration of quercetin, a reference antioxidant. These antioxidants are also superior to quercetin in protecting human skin keratinocytes against tert-butylhydroperoxide-induced oxidative stress. While XH antioxidant activity in model biological systems is consistent with the structure-activity relationship, their response is also modulated by the localization of XH and by structural factors. PMID:21475761

Santos, Clementina M M; Silva, Artur M S; Filipe, Paulo; Santus, René; Patterson, Larry K; Mazière, Jean-Claude; Cavaleiro, José A S; Morlière, Patrice

2011-04-08

382

Discovery of a new class of highly potent inhibitors of acid ceramidase: synthesis and structure-activity relationship (SAR).  

PubMed

Acid ceramidase (AC) is an intracellular cysteine amidase that catalyzes the hydrolysis of the lipid messenger ceramide. By regulating ceramide levels in cells, AC may contribute to the regulation of cancer cell proliferation and senescence and to the response to cancer therapy. We recently identified the antitumoral agent carmofur (4a) as the first nanomolar inhibitor of intracellular AC activity (rat AC, IC50 = 0.029 ?M). In the present work, we expanded our initial structure-activity relationship (SAR) studies around 4a by synthesizing and testing a series of 2,4-dioxopyrimidine-1-carboxamides. Our investigations provided a first elucidation of the structural features of uracil derivatives that are critical for AC inhibition and led us to identify the first single-digit nanomolar inhibitors of this enzyme. The present results confirm that substituted 2,4-dioxopyrimidine-1-carboxamides are a novel class of potent inhibitors of AC. Selected compounds of this class may represent useful probes to further characterize the functional roles of AC. PMID:23614460

Pizzirani, Daniela; Pagliuca, Chiara; Realini, Natalia; Branduardi, Davide; Bottegoni, Giovanni; Mor, Marco; Bertozzi, Fabio; Scarpelli, Rita; Piomelli, Daniele; Bandiera, Tiziano

2013-04-24

383

Decomposition of substituted alkoxy radicals--part I: a generalized structure-activity relationship for reaction barrier heights.  

PubMed

An update and expansion of our readily applicable structure-activity relationship (SAR) for predicting the barrier height E(b) to decomposition by beta C-C scission of (substituted) alkoxy radicals is presented. Such alkoxy radicals are key intermediates in the atmospheric oxidation of volatile organic compounds, and a correct description of their chemistry is vital to the understanding of atmospheric chemistry; nevertheless, experimental data on these reactions remain scarce. The SAR is based on quantum chemical characterizations of a large set of alkoxy radicals, and accommodates alkoxy radicals with alkyl- (-R), oxo- (=O), hydroxy- (-OH), hydroperoxy (-OOH), alkoxy (-OR), alkylperoxy- (-OOR), nitroso- (-NO), nitro- (-NO2), nitrosooxy- (-ONO), and nitroxy- (-ONO2) functionalities, as well as 3- to 6-membered rings and some unsaturated side chains. The SAR expresses the barrier height to decomposition, E(b) = 17.9 kcal mol(-1) + Sigma N(s) x F(s), as a linear function of the number N(s) of these substituents on the relevant carbons, and the substituent-specific activities F(s) derived from the quantum chemical calculations, allowing facile predictions based solely on the molecular structure. For low barriers, < or = 7 kcal mol(-1), a simple curvature correction is required. The SAR-predicted barrier height E(b) can be used to predict the high-pressure rate coefficient for alkoxy decomposition k(diss) at or around 298 K. PMID:19812826

Vereecken, L; Peeters, J

2009-08-04

384

Anticoagulant sulfated polysaccharides: Part I. Synthesis and structure–activity relationships of new pullulan sulfates  

Microsoft Academic Search

In order to develop new anticoagulants as potential heparin alternatives, two pullulans with different molecular weight (MW) were used as starting polymers for the partial synthesis of a structurally new class of sulfated polysaccharides. Sulfation of these linear ?-1,4-\\/1,6-glucans was carried out by a method with a SO3–pyridine complex in DMF, which had been optimized for the modification of ?-1,3-glucans.

S Alban; A Schauerte; G Franz

2002-01-01

385

Structure–activity relationships of lipopolysaccharide sequestration in guanylhydrazone-bearing lipopolyamines  

Microsoft Academic Search

The toxicity of Gram-negative bacterial endotoxin (lipopolysaccharide, LPS) resides in its structurally highly conserved glycolipid component called lipid A. Our major goal has been to develop small-molecules that would sequester LPS by binding to the lipid A moiety, so that it could be useful for the prophylaxis or adjunctive therapy of Gram-negative sepsis. We had previously identified in rapid-throughput screens

Wenyan Wu; Diptesh Sil; Michal L. Szostak; Subbalakshmi S. Malladi; Hemamali J. Warshakoon; Matthew R. Kimbrell; Jens R. Cromer; Sunil A. David

2009-01-01

386

Insights into structure-activity relationship of GABAA receptor modulating coumarins and furanocoumarins  

PubMed Central

The coumarins imperatorin and osthole are known to exert anticonvulsant activity. We have therefore analyzed the modulation of GABA-induced chloride currents (IGABA) by a selection of 18 coumarin derivatives on recombinant ?1?2?2S GABAA receptors expressed in Xenopus laevis oocytes by means of the two-microelectrode voltage clamp technique. Osthole (EC50=14±1 ?M) and oxypeucedanin (EC50=25±8 ?M) displayed the highest efficiency with IGABA potentiation of 116±4% and 547±56%, respectively. IGABA enhancement by osthole and oxypeucedanin was not inhibited by flumazenil (1 ?M) indicating an interaction with a binding site distinct from the benzodiazepine binding site. In general, prenyl residues are essential for the positive modulatory activity, while longer side chains or bulkier residues (e.g. geranyl residues) diminish IGABA modulation. Generation of a binary classification tree revealed the importance of polarisability, which is sufficient to distinguish actives from inactives. A 4-point pharmacophore model based on oxypeucedanin – comprising three hydrophobic and one aromatic feature – identified 6 out of 7 actives as hits. In summary, (oxy-)prenylated coumarin derivatives from natural origin represent new GABAA receptor modulators.

Singhuber, Judith; Baburin, Igor; Ecker, Gerhard F.; Kopp, Brigitte; Hering, Steffen

2011-01-01

387

Structure-activity relationships among the kanamycin aminoglycosides: role of ring I hydroxyl and amino groups.  

PubMed

The kanamycins form an important subgroup of the 4,6-disubstituted 2-deoxystreptamine aminoglycoside antibiotics, comprising kanamycin A, kanamycin B, tobramycin, and dibekacin. These compounds interfere with protein synthesis by targeting the ribosomal decoding A site, and they differ in the numbers and locations of amino and hydroxy groups of the glucopyranosyl moiety (ring I). We synthesized kanamycin analogues characterized by subtle variations of the 2' and 6' substituents of ring I. The functional activities of the kanamycins and the synthesized analogues were investigated (i) in cell-free translation assays on wild-type and mutant bacterial ribosomes to study drug-target interaction, (ii) in MIC assays to assess antibacterial activity, and (iii) in rabbit reticulocyte translation assays to determine activity on eukaryotic ribosomes. Position 2' forms an intramolecular H bond with O5 of ring II, helping the relative orientations of the two rings with respect to each other. This bond becomes critical for drug activity when a 6'-OH substituent is present. PMID:22948879

Salian, Sumantha; Matt, Tanja; Akbergenov, Rashid; Harish, Shinde; Meyer, Martin; Duscha, Stefan; Shcherbakov, Dmitri; Bernet, Bruno B; Vasella, Andrea; Westhof, Eric; Böttger, Erik C

2012-09-04

388

Structure-Activity Relationships among the Kanamycin Aminoglycosides: Role of Ring I Hydroxyl and Amino Groups  

PubMed Central

The kanamycins form an important subgroup of the 4,6-disubstituted 2-deoxystreptamine aminoglycoside antibiotics, comprising kanamycin A, kanamycin B, tobramycin, and dibekacin. These compounds interfere with protein synthesis by targeting the ribosomal decoding A site, and they differ in the numbers and locations of amino and hydroxy groups of the glucopyranosyl moiety (ring I). We synthesized kanamycin analogues characterized by subtle variations of the 2? and 6? substituents of ring I. The functional activities of the kanamycins and the synthesized analogues were investigated (i) in cell-free translation assays on wild-type and mutant bacterial ribosomes to study drug-target interaction, (ii) in MIC assays to assess antibacterial activity, and (iii) in rabbit reticulocyte translation assays to determine activity on eukaryotic ribosomes. Position 2? forms an intramolecular H bond with O5 of ring II, helping the relative orientations of the two rings with respect to each other. This bond becomes critical for drug activity when a 6?-OH substituent is present.

Salian, Sumantha; Matt, Tanja; Akbergenov, Rashid; Harish, Shinde; Meyer, Martin; Duscha, Stefan; Shcherbakov, Dmitri; Bernet, Bruno B.; Vasella, Andrea; Westhof, Eric

2012-01-01

389

Structure-activity relationships of xanthocillin derivatives as thrombopoietin receptor agonist.  

PubMed

Xanthocillin derivatives, which show thrombopoietin receptor agonist activity, were synthesized through our developed method. Bioassay data suggest the importance of alkene geometry, the presence of substituents at the benzene ring that support hydrophobic character, and the moderate size of the molecule. One of the two isonitrile group of the natural product appears to be dispensable. PMID:17256473

Yamaguchi, Takahiro; Miyake, Yumi; Miyamura, Atsushi; Ishiwata, Norihisa; Tatsuta, Kuniaki

2006-11-01

390

Synthesis and structure-activity relationship (SAR) study of 4-azabenzoxazole analogues as H3 antagonists.  

PubMed

The synthesis and SAR of a novel series of 4-azabenzoxazole histamine H(3) antagonists is described. Introduction of substituted phenyl, pyridyl and fused heterocyclic groups to the 6-position of the 4-azabenzoxazole core gave a series of compounds with good H(3) antagonist activity in both ex vivo and in vivo assays. PMID:22326166

Shao, Ning; Aslanian, Robert; West, Robert E; Williams, Shirley M; Wu, Ren-Long; Hwa, Joyce; Sondey, Christopher; Lachowicz, Jean; Palani, Anandan

2012-01-24

391

Structure-activity relationships and molecular modeling of 1,2,4-triazoles as adenosine receptor antagonists  

PubMed Central

The structure-activity relationship (SAR) for a novel class of 1,2,4-triazole antagonists of the human A2A adenosine receptor (hA2AAR) was explored. Thirty-three analogs of a ligand that was discovered in a structure-based virtual screen against the hA2AAR were tested in hA1, A2A, and A3 radioligand binding assays and in functional assays for the A2BAR subtype. As a series of closely related analogs of the initial lead, 1, did not display improved binding affinity or selectivity, molecular docking was used to guide the selection of more distantly related molecules. This resulted in the discovery of 32, a hA2AAR antagonist (Ki 200 nM) with high ligand efficiency. In the light of the SAR for the 1,2,4-triazole scaffold, we also investigated the binding mode of these compounds based on docking to several A2AAR crystal structures.

Carlsson, Jens; Tosh, Dilip K.; Phan, Khai; Gao, Zhan-Guo; Jacobson, Kenneth A.

2012-01-01

392

Structure-activity relationships and molecular modeling of 1,2,4-triazoles as adenosine receptor antagonists.  

PubMed

The structure-activity relationship (SAR) for a novel class of 1,2,4-triazole antagonists of the human A(2A) adenosine receptor (hA(2A)AR) was explored. Thirty-three analogs of a ligand that was discovered in a structure-based virtual screen against the hA(2A)AR were tested in hA(1), A(2A), and A(3) radioligand binding assays and in functional assays for the A(2B)AR subtype. As a series of closely related analogs of the initial lead, 1, did not display improved binding affinity or selectivity, molecular docking was used to guide the selection of more distantly related molecules. This resulted in the discovery of 32, a hA(2A)AR antagonist (K(i) 200 nM) with high ligand efficiency. In the light of the SAR for the 1,2,4-triazole scaffold, we also investigated the binding mode of these compounds based on docking to several A(2A)AR crystal structures. PMID:23342198

Carlsson, Jens; Tosh, Dilip K; Phan, Khai; Gao, Zhan-Guo; Jacobson, Kenneth A

2012-07-30

393

Comparative analysis of local and consensus quantitative structure-activity relationship approaches for the prediction of bioconcentration factor.  

PubMed

Quantitative structure-activity relationships (QSARs) are broadly classified as global or local, depending on their molecular constitution. Global models use large and diverse training sets covering a wide range of chemical space. Local models focus on smaller structurally or chemically similar subsets that are conventionally selected by human experts or alternatively using clustering analysis. The current study focuses on the comparative analysis of different clustering algorithms (expectation-maximization, K-means and hierarchical) for seven different descriptor sets as structural characteristics and two rule-based approaches to select subsets for designing local QSAR models. A total of 111 local QSAR models are developed for predicting bioconcentration factor. Predictions from local models were compared with corresponding predictions from the global model. The comparison of coefficients of determination (r(2)) and standard deviations for local models with similar subsets from the global model show improved prediction quality in 97% of cases. The descriptor content of derived QSARs is discussed and analyzed. Local QSAR models were further consolidated within the framework of consensus approach. All different consensus approaches increased performance over the global and local models. The consensus approach reduced the number of strongly deviating predictions by evening out prediction errors, which were produced by some local QSARs. PMID:23410132

Piir, G; Sild, S; Maran, U

2013-02-14

394

Structure-activity relationship of ETH during ecdysis in the tobacco hornworm, Manduca sexta.  

PubMed

In insects, ecdysis or shedding of the old cuticle, consists of a series of behaviors that are regulated by the coordinated actions of a number of neuropeptides, one of which is ecdysis triggering hormone (ETH). ETH acts directly on central pattern generators of the abdominal ganglia to trigger onset of pre-ecdysis behaviors, as well as indirectly to activate release of eclosion hormone, thereby inducing onset of ecdysis behaviors through a cGMP-mediated mechanism. We assessed the minimal C-terminal amino acids required for biological activity of ETH, by assessing: (i) onset of pre-ecdysis and ecdysis behaviors in vivo, after injection of peptide analogs, (ii) onset of fictive pre-ecdysis and ecdysis motor patterns in vitro, as recorded extracellularly, after incubation of the CNS with the peptide analogs, and (iii) accumulation of cGMP within cells of the abdominal ganglia, as assessed immunohistochemically. Amidation of ETH at the C-terminus was required to elicit a biological response in vivo and in vitro, as well as an accumulation of cGMP within the CNS. The five amino acid amidated C-terminus of ETH (NIPRMamide) was the minimal moiety able to induce a robust pre-ecdysis response in vivo and in vitro, while a seven amino acid core (NKNIPRMa) was required for induction of ecdysis, including accumulation of cGMP immunoreactivity within the CNS. Analogs smaller than 12 amino acids in length were only active at very high concentrations in vivo, suggesting that smaller fragments might be susceptible to hemolymph degradation. Some alanine substitutions or removal of internal amino acids altered the activity of ETH, as well as the time of onset of ecdysis behaviors, suggesting that internal amino acids play a role in maintaining proper folding of the peptide for successful binding or activity at the ETH receptor. PMID:16188346

Wells, Cornell; Aparicio, Katherine; Salmon, Arthur; Zadel, Ari; Fuse, Megumi

2005-09-26

395

Structure/antileishmanial activity relationship study of naphthoquinones and dependency of the mode of action on the substitution patterns.  

PubMed

A series of naphthoquinones was tested for activity against both extracellular promastigote and intracellular amastigote Leishmania major GFP in vitro. In parallel, the compounds were evaluated for cytotoxic effects against bone marrow-derived macrophages (BMM ?) as a mammalian host cell control. Most of the compounds noticeably inhibited the growth of extracellular parasites (IC (50) 0.5 to 6?µM) and the intracellular survival of L. major GFP amastigotes (IC (50) 1 to 7?µM) when compared with the antileishmanial drug amphotericin B (IC (50) of 2.5 and 0.2?µM, respectively). In general, antiprotozoal activity and host cell cytotoxicity seemed to increase in parallel. Conspicuously, the cytotoxic effect was less pronounced on infected host cells when compared with that on noninfected cells. Concerning structure/activity relationships for the tested naphthoquinones, some interesting structural features emerged from this study. Introduction of a methyl or methoxyl group at C-2 of the parent 1,4-naphthoquinone slightly increased the antileishmanial activity against clinically relevant amastigotes, while the presence of a hydroxyl function in this position dramatically reduced the effectiveness. In contrast, hydroxylation at C-5 and dihydroxy substitution at C-5 and C-8 significantly enhanced the antiprotozoal activity. Similarly, the presence of a side chain hydroxyl group PERI to a carbonyl function as represented in the series of shikonin/alkannin derivatives increased the activity when compared with substituted analogs. Within the series of naphthoquinones tested, the dimeric mixture of vaforhizin and isovaforhizin showed the highest activity IN VITRO against the clinically relevant intracellular amastigote with an IC (50) of 1.1?µM. With IC (50) values mostly in the range of 1-3?µM, the shikonin/alkannin derivatives proved to be similarly considerably leishmanicidal. None of the compounds tested was capable to induce NO production known to play a crucial role in the host resistance against intracellular pathogens, excluding activation of microbicidal mechanisms in macrophages. The mode of action apparently depended on the substitution pattern, associated with the electrophilicity of the naphthoquinone or the efficiency of redox cycling. Conspicuously, members oxygenated in the quinone ring proved to be leishmanicidal when coincubated with glutathione, while the majority of the remaining compounds lost activity. PMID:21800278

Ali, Ahmad; Assimopoulou, Andreana Nikolaos; Papageorgiou, Vassilios Peter; Kolodziej, Herbert

2011-07-28

396

Further data on the structure of brown seaweed fucans: relationships with anticoagulant activity  

Microsoft Academic Search

The composition, molecular weight (MW), anticoagulant activity and nuclear magnetic resonance spectra of various low-molecular-weight fucans (LMWFs) obtained by partial hydrolysis or radical depolymerization of a crude fucoidan extracted from the brown seaweed Ascophyllum nodosum are compared. Fucose units were found mainly sulfated at O-2, to a lesser extent at O-3, and only slightly at O-4, contrary to previously published

Lionel Chevolot; Alain Foucault; Frederic Chaubet; Nelly Kervarec; Corinne Sinquin; Anne-Marie Fisher; Catherine Boisson-Vidal

1999-01-01

397

Structure–activity relationships for inhibition of human 5?-reductases by polyphenols  

Microsoft Academic Search

The enzyme steroid 5?-reductase (EC 1.3.99.5) catalyzes the NADPH-dependent reduction of the double bond of a variety of 3-oxo-?4 steroids including the conversion of testosterone to 5?-dihydrotestosterone. In humans, 5?-reductase activity is critical for certain aspects of male sexual differentiation, and may be involved in the development of benign prostatic hyperplasia, alopecia, hirsutism, and prostate cancer. Certain natural products contain

Richard A. Hiipakka; Han-Zhong Zhang; Wei Dai; Qing Dai; Shutsung Liao

2002-01-01

398

Side Effects of Anabolic Androgenic Steroids: Pathological Findings and Structure–Activity Relationships  

Microsoft Academic Search

\\u000a Side effects of anabolic steroids with relevance in forensic medicine are mainly due to life-threatening health risks with\\u000a potential fatal outcome and cases of uncertain limitations of criminal liability after steroid administration. Both problems\\u000a are typically associated with long-term abuse and excessive overdose of anabolic steroids. Side effects may be due to direct\\u000a genomic or nongenomic activities (myotrophic, hepatotoxic), can

Andreas Büttner; Detlef Thieme

399

Taxane analogues against breast cancer: a quantitative structure-activity relationship study.  

PubMed

Breast cancer is the second leading cause of cancer death among women in the United States. Two taxane analogues, taxol and taxotere, are the most important antimitotic drugs currently in clinical use for the treatment of breast cancers. However, recent reports have indicated that the use of these drugs often results in various undesired side effects as well as multi-drug resistance. These limitations have led to the development of new taxane derivatives with fewer side effects, superior pharmacological properties, and improved anticancer activity to maximize the induced benefits for breast cancer patients. Herein, four series of taxane derivatives were used to correlate their inhibitory activities against breast cancer cells with their hydrophobic and steric properties in order to understand their chemical-biological interactions. The resulting QSARs show that the inhibitory activities of taxane analogues against breast cancers are mainly dependent either on their hydrophobicity or the hydrophobic/molar refractivity descriptor of their substituents. A parabolic correlation with MR(Y) is the most encouraging example, in which the optimum value of this parameter is well defined. We believe this correlation may prove to be an adequate predictive model that can help provide guidance in design and synthesis and subsequently yield highly specific compounds that may have high anti-breast-cancer activity with fewer side effects and superior pharmacological properties. On the basis of this