Synthesis and analgesic activity of some quinazoline analogs of anpirtoline.

PubMed

Rádl, S; Hezky, P; Proska, J; Krejcí, I

2000-11-01

New condensed derivatives of anpirtoline, in which the pyridine ring is replaced with quinoline, quinazoline, 7-chloroquinoline, and 7-chloroquinazoline nuclei, have been synthesized. Their receptor binding profiles (5-HT1A, 5-HT1B) and analgesic activity (hot plate, acetic acid induced writhing) have been studied. The analgesic activity of compounds 4e-4g, and 4l are at least comparable to that of clinically used drugs flupirtine and tramadol under the same conditions.

Biologically active quinoline and quinazoline alkaloids part I.

PubMed

Shang, Xiao-Fei; Morris-Natschke, Susan L; Liu, Ying-Qian; Guo, Xiao; Xu, Xiao-Shan; Goto, Masuo; Li, Jun-Cai; Yang, Guan-Zhou; Lee, Kuo-Hsiung

2018-05-01

Quinoline and quinazoline alkaloids, two important classes of N-based heterocyclic compounds, have attracted tremendous attention from researchers worldwide since the 19th century. Over the past 200 years, many compounds from these two classes were isolated from natural sources, and most of them and their modified analogs possess significant bioactivities. Quinine and camptothecin are two of the most famous and important quinoline alkaloids, and their discoveries opened new areas in antimalarial and anticancer drug development, respectively. In this review, we survey the literature on bioactive alkaloids from these two classes and highlight research achievements prior to the year 2008 (Part I). Over 200 molecules with a broad range of bioactivities, including antitumor, antimalarial, antibacterial and antifungal, antiparasitic and insecticidal, antiviral, antiplatelet, anti-inflammatory, herbicidal, antioxidant and other activities, were reviewed. This survey should provide new clues or possibilities for the discovery of new and better drugs from the original naturally occurring quinoline and quinazoline alkaloids. © 2017 Wiley Periodicals, Inc.

Novel quinazoline and acetamide derivatives as safe anti-ulcerogenic agent and anti-ulcerative colitis activity.

PubMed

Alasmary, Fatmah A S; Awaad, Amani S; Alafeefy, Ahmed M; El-Meligy, Reham M; Alqasoumi, Saleh I

2018-01-01

Two novel quinazoline derivatives named as; 3-[(4-hydroxy-3-methoxy-benzylidene)-amino]-2- p- tolyl-3 H -quinazolin-4-one ( 5 ) and 2- p -Tolyl-3-[3,4,5-trimethoxy-benzylidene-amino]-3 H -quinazolin-4-one ( 6 ) in addition to one acetamide derivative named as 2-(2-Hydroxycarbonylphenylamino)- N -(4-aminosulphonylphenyl) 11 were synthesized, and evaluated for their anti-ulcerogenic & Anti-Ulcerative colitis activities. All of the three compounds showed curative activity against acetic acid induced ulcer model at a dose of 50 mg/kg, they produced 65%, 85% & 57.74% curative ratio for compounds 5 , 6 & 11 respectively. The effect of the tested compounds 5 , 6 & 11 at dose 50 mg/kg were significantly (P < 0.01) more effective than dexamesathone (0.1 mg/kg) in reducing all parameters. Compounds showed curative activity of for peptic ulcer (induced by absolute alcohol (at a dose of 50 mg/kg, it produced Curative of control ulcer 56.00%, 61.70% & 87.1% for compounds 5 , 6 & 11 respectively at dose 50 mg/kg, while the standard drug (Omeprazole 20 mg/kg) produced 33.3%. In both tests, the activity of our target compounds were higher than the standard drugs used for treatment of peptic ulcer and ulcerative colitis. No side effects were reported on liver and kidney functions upon prolonged oral administration of this compounds.

Synthesis and evaluation of novel 18 F-labeled quinazoline derivatives with low lipophilicity for tumor PET imaging.

PubMed

Chong, Yan; Chang, Jin; Zhao, Wenwen; He, Yong; Li, Yuqiao; Zhang, Huabei; Qi, Chuanmin

2018-02-01

Four novel 18 F-labeled quinazoline derivatives with low lipophilicity, [ 18 F]4-(2-fluoroethoxy)-6,7-dimethoxyquinazoline ([ 18 F]I), [ 18 F]4-(3-((4-(2-fluoroethoxy)-7-methoxyquinazolin-6-yl)oxy)propyl)morpholine ([ 18 F]II), [ 18 F]4-(2-fluoroethoxy)-7-methoxy-6-(2-methoxyethoxy)quinazoline ([ 18 F]III), and [ 18 F]4-(2-fluoroethoxy)-6,7-bis(2-methoxyethoxy)quinazoline ([ 18 F]IV), were synthesized via a 2-step radiosynthesis procedure with an overall radiochemical yield of 10% to 38% (without decay correction) and radiochemical purities of >98%. The lipophilicity and stability of labeled compounds were tested in vitro. The log P values of the 4 radiotracers ranged from 0.52 to 1.07. We then performed ELISA to measure their affinities to EGFR-TK; ELISA assay results indicated that each inhibitor was specifically bounded to EGFR-TK in a dose-dependent manner. The EGFR-TK autophosphorylation IC 50 values of [ 18 F]I, [ 18 F]II, [ 18 F]III, and [ 18 F]IV were 7.732, 0.4698, 0.1174, and 0.1176 μM, respectively. All labeled compounds were evaluated via cellular uptake and blocking studies in HepG2 cell lines in vitro. Cellular uptake and blocking experiment results indicated that [ 18 F]I and [ 18 F]III had excellent cellular uptake at 120-minute postinjection in HepG2 carcinoma cells (51.80 ± 3.42%ID/mg protein and 27.31 ± 1.94%ID/mg protein, respectively). Additionally, biodistribution experiments in S180 tumor-bearing mice in vivo indicated that [ 18 F]I had a very fast clearance in blood and a relatively high uptake ratio of tumor to blood (4.76) and tumor to muscle (1.82) at 60-minute postinjection. [ 18 F]III had a quick clearance in plasma, and its highest uptake ratio of tumor to muscle was 2.55 at 15-minute postinjection. These experimental results and experiences were valuable for the further exploration of novel radiotracers of quinazoline derivatives. Copyright © 2017 John Wiley & Sons, Ltd.

Disposable DNA biosensor with the carbon nanotubes-polyethyleneimine interface at a screen-printed carbon electrode for tests of DNA layer damage by quinazolines.

PubMed

Galandová, Júlia; Ovádeková, Renáta; Ferancová, Adriana; Labuda, Ján

2009-06-01

A screen-printed carbon working electrode within a commercially available screen-printed three-electrode assembly was modified by using a composite of multiwalled carbon nanotubes (MWCNT) dispersed in polyethylenimine (PEI) followed by covering with the calf thymus dsDNA layer. Several electrochemical methods were used to characterize the biosensor and to evaluate damage to the surface-attached DNA: square wave voltammetry of the [Ru(bpy)(3)](2+) redox indicator and mediator of the guanine moiety oxidation, cyclic voltammetry and electrochemical impedance spectroscopy in the presence of the [Fe(CN)(6)](3-/4-) indicator in solution. Due to high electroconductivity and large surface area of MWCNT and positive charge of PEI, the MWCNT-PEI composite is an advantageous platform for the DNA immobilization by the polyelectrolyte complexation and its voltammetric and impedimetric detection. In this respect, the MWCNT-PEI interface exhibited better properties than the MWCNT-chitosan one reported from our laboratory previously. A deep DNA layer damage at incubation of the biosensor in quinazoline solution was found, which depends on the quinazoline concentration and incubation time.

Benzo[g]quinazolin-based scaffold derivatives as dual EGFR/HER2 inhibitors.

PubMed

Ghorab, Mostafa M; Alsaid, Mansour S; Soliman, Aiten M; Al-Mishari, Abdullah A

2018-12-01

Targeting EGFR has proven to be beneficial in the treatment of several types of solid tumours. So, a series of novel 2-(4-oxo-3-(4-sulfamoylphenyl)-3,4-dihydrobenzo[g]quinazolin-2-ylthio)-N-substituted acetamide 5-19 were synthesised from the starting material 4-(2-mercapto-4-oxobenzo[g]quinazolin-3(4H)-yl) benzenesulfonamide 4, to be evaluated as dual EGFR/HER2 inhibitors. The target compounds 5-19, were screened for their cytotoxic activity against A549 lung cancer cell line. The percentage inhibition of EGFR enzyme was measured and compared with erlotinib as the reference drug. Compounds 6, 8, 10, and 16 showed excellent EGFR inhibitory activity and were further selected for screening as dual EGFR/HER2 inhibitors. The four selected compounds showed IC 50 ranging from 0.009 to 0.026 µM for EGFR and 0.021 to 0.069 µM for the HER2 enzyme. Compound 8 was found to be the most potent in this study with IC 50 0.009 and 0.021 µM for EGFR and HER2, respectively.

Search for Compounds with Hypoglycemic Activity in the Series of 1-[2-(1H-Tetrazol-5-yl)-R1-phenyl]-3-R2-phenyl(ethyl)ureas and R1-Tetrazolo[1,5-c]quinazolin-5(6H)-ones

PubMed Central

Antypenko, Oleksii M.; Kovalenko, Sergiy I.; Zhernova, Galina O.

2016-01-01

Methods of 1-[2-(1H-tetrazol-5-yl)-R1-phenyl]-3-R2-phenyl(ethyl)ureas and R1-tetrazolo[1,5-c]quinazolin-5(6H)-ones synthesis were designed. IR, LC-MS, 1H NMR, and elemental analysis data evaluated the structure and purity of the obtained compounds. Different products, depending on the reaction conditions, were distinguished and discussed. The preliminary hypoglycemic activity of 36 synthesized compounds was revealed. Docking studies to 11β-hydroxysteroid dehydrogenase 1, γ-peroxisome proliferator-activated receptor, and dipeptidyl peptidase-4 were conducted. Eight of these substances were further tested on glucocorticoid-induced insulin resistance models, namely glucose tolerance, oral rapid insulin, and adrenalin tests. One of the most active compounds turned out to be tetrazolo[1,5-c]quinazolin-5(6H)-one 3.1, exceeding the reference drugs Metformin (50 and 200 mg/kg) and Gliclazide (50 mg/kg). PMID:27222601

Synthesis, molecular docking, DFT calculations and cytotoxicity activity of benzo[g]quinazoline derivatives in choline chloride-urea

NASA Astrophysics Data System (ADS)

Lakshmanan, Sivalingam; Govindaraj, Dharman; Ramalakshmi, Narayanan; Antony, S. Arul

2017-12-01

Green and highly efficient one-pot three component approach for the synthesis of benzo[g]quinazoline derivatives (6a-g) using Choline chloride-urea (DES). Synthesized compounds 6b and 6g showed the most potent biological activity against A549 lung cancer cell line. Docking simulation was performed to position compounds 6b and 6g showed the greater affinity for anaplastic lymphoma kinase (ALK) receptor. Quantum chemical studies were carried out on these compounds to understand the structural features essential for activity using DFT/6-31G level of theory.

Identification of quinazoline based inhibitors of IRAK4 for the treatment of inflammation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Smith, Graham F.; Altman, Michael D.; Andresen, Brian

Interleukin-1 receptor associated kinase 4 (IRAK4) has been implicated in IL-1R and TLR based signaling. Therefore selective inhibition of the kinase activity of this protein represents an attractive target for the treatment of inflammatory diseases. Medicinal chemistry optimization of high throughput screening (HTS) hits with the help of structure based drug design led to the identification of orally-bioavailable quinazoline based IRAK4 inhibitors with excellent pharmacokinetic profile and kinase selectivity. These highly selective IRAK4 compounds show activity in vivo via oral dosing in a TLR7 driven model of inflammation.

Novel Mps1 kinase inhibitors: from purine to pyrrolopyrimidine and quinazoline leads.

PubMed

Bursavich, Matthew G; Dastrup, David; Shenderovich, Mark; Yager, Kraig M; Cimbora, Daniel M; Williams, Brandi; Kumar, D Vijay

2013-12-15

Mps1, also known as TTK, is a mitotic checkpoint protein kinase that has become a promising new target of cancer research. In an effort to improve the lead-likeness of our recent Mps1 purine lead compounds, a scaffold hopping exercise has been undertaken. Structure-based design, principles of conformational restriction, and subsequent scaffold hopping has led to novel pyrrolopyrimidine and quinazoline Mps1 inhibitors. These new single-digit nanomolar leads provide the basis for developing potent, novel Mps1 inhibitors with improved drug-like properties. Copyright © 2013 Elsevier Ltd. All rights reserved.

Synthesis and SAR of 1-acetanilide-4-aminopyrazole-substituted quinazolines: selective inhibitors of Aurora B kinase with potent anti-tumor activity.

PubMed

Foote, Kevin M; Mortlock, Andrew A; Heron, Nicola M; Jung, Frédéric H; Hill, George B; Pasquet, Georges; Brady, Madeleine C; Green, Stephen; Heaton, Simon P; Kearney, Sarah; Keen, Nicholas J; Odedra, Rajesh; Wedge, Stephen R; Wilkinson, Robert W

2008-03-15

A new class of 1-acetanilide-4-aminopyrazole-substituted quinazoline Aurora kinase inhibitors has been discovered possessing highly potent cellular activity. Continuous infusion into athymic mice bearing SW620 tumors of the soluble phosphate derivative 2 led to dose-proportional exposure of the des-phosphate compound 8 with a high-unbound fraction. The combination of potent cell activity and high free-drug exposure led to pharmacodynamic changes in the tumor at low doses, indicative of Aurora B-kinase inhibition and a reduction in tumor volume.

Synthesis and SAR studies of novel 2-(6-aminomethylaryl-2-aryl-4-oxo-quinazolin-3(4H)-yl)acetamide vasopressin V1b receptor antagonists.

PubMed

Napier, Susan E; Letourneau, Jeffrey J; Ansari, Nasrin; Auld, Douglas S; Baker, James; Best, Stuart; Campbell-Wan, Leigh; Chan, Ray; Craighead, Mark; Desai, Hema; Ho, Koc-Kan; MacSweeney, Cliona; Milne, Rachel; Richard Morphy, J; Neagu, Irina; Ohlmeyer, Michael H J; Pick, Jack; Presland, Jeremy; Riviello, Chris; Zanetakos, Heather A; Zhao, Jiuqiao; Webb, Maria L

2011-06-15

Synthesis and structure-activity relationships (SAR) of a novel series of vasopressin V(1b) antagonists are described. 2-(6-Aminomethylaryl-2-aryl-4-oxo-quinazolin-3(4H)-yl)acetamide have been identified with low nanomolar affinity for the V(1b) receptor and good selectivity with respect to related receptors V(1a), V(2) and OT. Optimised compound 16 shows a good pharmacokinetic profile and activity in a mechanistic model of HPA dysfunction. Copyright © 2011 Elsevier Ltd. All rights reserved.

Copper-Catalyzed Domino Three-Component Approach for the Assembly of 2-Aminated Benzimidazoles and Quinazolines.

PubMed

Tran, Lam Quang; Li, Jihui; Neuville, Luc

2015-06-19

A copper-promoted three-component synthesis of 2-aminobenzimidazoles (1) or of 2-aminoquinazolines (2) involving cyanamides, arylboronic acids, and amines has been developed. The operationally simple oxidative process, performed in the presence of K2CO3, a catalytic amount of CuCl2·2H2O, 2,2'-bipyridine, and an O2 atmosphere (1 atm), allows the rapid assembly of either benzimidazoles or quinazolines starting from aryl- or benzyl-substituted cyanamides, respectively. In this process, the copper promotes the formation of three bonds, two C-N bonds, and an additional bond resulting from C-H functionalization event.

Antipsychotic potential of quinazoline ErbB1 inhibitors in a schizophrenia model established with neonatal hippocampal lesioning.

PubMed

Mizuno, Makoto; Iwakura, Yuriko; Shibuya, Masako; Zheng, Yingjun; Eda, Takeyoshi; Kato, Taisuke; Takasu, Yohei; Nawa, Hiroyuki

2010-01-01

Hyper-signaling of the epidermal growth factor receptor family (ErbB) is implicated in the pathophysiology of schizophrenia. Various quinazoline inhibitors targeting ErbB1 or ErbB2 - 4 have been developed as anti-cancer agents and might be useful for antipsychotic treatment. In the present study, we used an animal model of schizophrenia established by neonatal hippocampal lesioning and evaluated the neurobehavioral consequences of ErbB1-inhibitor treatment. Subchronic administration of the ErbB1 inhibitor ZD1839 to the cerebroventricle of rats receiving neonatal hippocampal lesioning ameliorated deficits in prepulse inhibition as well as those in the latent inhibition of tone-dependent fear learning. There were no apparent adverse effects on basal learning scores or locomotor activity, however. The administration of other ErbB1 inhibitors, PD153035 and OSI-774, similarly attenuated the prepulse inhibition impairment of this animal model. In parallel, there were decreases in ErbB1 phosphorylation in animals treated with ErbB1 inhibitors. These results indicate an antipsychotic potential of quinazoline ErbB1 inhibitors. ErbB receptor tyrosine kinases may be novel therapeutic targets for schizophrenia or its related psychotic symptoms.

4-amino-1H-benzo[g]quinazoline-2-one: a fluorescent analog of cytosine to probe protonation sites in triplex forming oligonucleotides.

PubMed

Godde, F; Toulmé, J J; Moreau, S

2000-08-01

We developed a new fluorescent analog of cytosine, the 4-amino-1H-benzo[g]quinazoline-2-one, which constitute a probe sensitive to pH. The 2'-O-Me ribonucleoside derivative of this heterocycle was synthesized and exhibited a fluorescence emission centered at 456 nm, characterized by four major excitation maxima (250, 300, 320 and 370 nm) and a fluorescence quantum yield of Phi = 0.62 at pH 7.1. The fluorescence emission maximum shifted from 456 to 492 nm when pH was decreased from 7.1 to 2.1. The pK(a) (4) was close to that of cytosine (4.17). When introduced in triplex forming oligonucleotides this new nucleoside can be used to reveal the protonation state of triplets in triple-stranded structures. Complex formation was detected by a significant quenching of fluorescence emission (approximately 88%) and the N-3 protonation of the quinazoline ring by a shift of the emission maximum from 485 to 465 nm. Using this probe we unambiguously showed that triplex formation of the pyrimidine motif does not require the protonation of all 4-amino-2-one pyrimidine rings.

New diols with imidazoquinazoline ring

NASA Astrophysics Data System (ADS)

Szyszkowska, Agnieszka; Klasek, Antonin; Pawlędzio, Sylwia; Trzybiński, Damian; Woźniak, Krzysztof; Zarzyka, Iwona

2018-02-01

The objective of these studies was to synthesize and characterize new diols with an imidazoquinazoline ring. New diols were obtained in reactions of 2,6-bis-(ethoxycarbonylmethyl)-1-phenylimidazo[1,5-c]quinazoline-3,5-dione with excess of ethylene glycol or in reaction of 1-phenyl-2H,6H-imidazo[1,5-c]quinazoline-3,5-dione with 2-M excess of ethylene oxide. The products were isolated at high yield and characterized by instrumental methods (IR, 1H- and 13C-NMR, MS-ESI, UV, TGA). The structure of 2,6-bis(2-hydroxyethyl)-1-phenylimidazo[1,5-c]quinazoline-3,5-dione (BEFIQ) was also investigated by single-crystal X-ray diffraction. BEFIQ crystallizes in the monoclinic P21/n space group with two molecules in the asymmetric unit of the crystal lattice. The nature of the packing of molecules in the crystal lattice of BEFIQ was investigated by Hirshfeld surface analysis. The described methods enable the synthesis of new diols with an imidazoquinazoline ring. The new diols are quite soluble in typical organic solvents. Therefore, they can be used as raw materials for the synthesis of thermally stable polymers, and they can also have biological activity.

6-Chloro-3-phenethyl-2-thioxo-2,3-di­hydro­quinazolin-4(1H)-one

PubMed Central

Hashim, Norhafizah Mohd; Osman, Hasnah; Rahim, Afidah Abdul; Yeap, Chin Sing; Fun, Hoong-Kun

2010-01-01

The asymmetric unit of the title quinazolinone compound, C16H13ClN2OS, consists of two crystallographically independent mol­ecules, A and B. The dihedral angles between the quinazoline and benzene rings are 16.88 (6) and 32.34 (6)° for mol­ecules A and B, respectively. In the crystal structure, mol­ecules A and B are linked by two bifurcated inter­molecular N—H⋯S and C—H⋯S hydrogen bonds. Pairs of mol­ecules are further linked by C—H⋯O and C—H⋯Cl hydrogen bonds into a chain aligned approximately along [110]. PMID:21580754

Divergent Syntheses of Isoquinolines and Indolo[1,2-a]quinazolines by Copper-Catalyzed Cascade Annulation from 2-Haloaryloxime Acetates with Active Methylene Compounds and Indoles.

PubMed

Jiang, Huanfeng; Yang, Jidan; Tang, Xiaodong; Wu, Wanqing

2016-03-04

A convenient and reliable method for the direct construction of isoquinolines is described. A series of isoquinoline derivatives were synthesized, with high chemo- and regioselectivities, via the copper-catalyzed cascade reaction of 2-haloaryloxime acetates with β-diketones, β-keto esters, and β-keto nitriles. This tandem annulation process features inexpensive catalysts, no need for additional ligands, and excellent functional group tolerance, which makes it have potential synthetic applications. Furthermore, this strategy could also be used to enter functionalized indolo[1,2-a]quinazolines by using indoles as the counterpart of the 2-haloaryloxime acetates.

Synthesis, anti-inflammatory evaluation and docking studies of some new fluorinated fused quinazolines.

PubMed

Balakumar, C; Lamba, P; Kishore, D Pran; Narayana, B Lakshmi; Rao, K Venkat; Rajwinder, K; Rao, A Raghuram; Shireesha, B; Narsaiah, B

2010-11-01

A series of novel 8/10-trifluoromethyl-substituted-imidazo[1,2-c] quinazolines have been synthesized and evaluated in vivo (rat paw edema) for their anti-inflammatory activity and in silico (docking studies) to recognize the hypothetical binding motif of the title compounds with the cyclooxygenase isoenzymes (COX-1 and COX-2) employing GOLD (CCDC, 4.0.1 version) software. The compounds, 9b and 10b, were found to have good anti-inflammatory activity [around 80% of the standard: indomethacin]. The binding mode of the title compounds has been proposed based on the docking studies. Crown Copyright © 2010. Published by Elsevier Masson SAS. All rights reserved.

Quinazolin-4-one derivatives as selective histone deacetylase-6 inhibitors for the treatment of Alzheimer's disease.

PubMed

Yu, Chao-Wu; Chang, Pei-Teh; Hsin, Ling-Wei; Chern, Ji-Wang

2013-09-12

Novel quinazolin-4-one derivatives containing a hydroxamic acid moiety were designed and synthesized. All compounds were subjected to histone deacetylase (HDAC) enzymatic assays to identify selective HDAC6 inhibitors with nanomolar IC50 values. (E)-3-(2-Ethyl-7-fluoro-4-oxo-3-phenethyl-3,4-dihydroquinazolin-6-yl)-N-hydroxyacrylamide, 4b, is the most potent HDAC6 inhibitor (IC50, 8 nM). In vitro, these compounds induced neurite outgrowth accompanied by growth-associated protein 43 expression, and they enhanced the synaptic activities of PC12 and SH-SY5Y neuronal cells without producing toxic or mitogenic effects. Several of the compounds dramatically increased nonhistone protein acetylation, specifically of α-tubulin. Some of the more potent HDAC6 inhibitors decreased zinc-mediated β-amyloid aggregation in vitro. N-Hydroxy-3-(2-methyl-4-oxo-3-phenethyl-3,4-dihydro-quinazolin-7-yl)-acrylamide, 3f, the most promising drug candidate, selectively inhibits HDAC6 (IC50, 29 nM), practically does not affect human ether-a-go-go-related membrane channel activity (IC50 >10 μM) or cytochrome P450 activity (IC50 >6.5 μM) in vitro, and significantly improves learning-based performances of mice with β-amyloid-induced hippocampal lesions.

Novel mutant-selective EGFR kinase inhibitors against EGFR T790M

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhou, Wenjun; Ercan, Dalia; Chen, Liang

2010-01-12

The clinical efficacy of epidermal growth factor receptor (EGFR) kinase inhibitors in EGFR-mutant non-small-cell lung cancer (NSCLC) is limited by the development of drug-resistance mutations, including the gatekeeper T790M mutation. Strategies targeting EGFR T790M with irreversible inhibitors have had limited success and are associated with toxicity due to concurrent inhibition of wild-type EGFR. All current EGFR inhibitors possess a structurally related quinazoline-based core scaffold and were identified as ATP-competitive inhibitors of wild-type EGFR. Here we identify a covalent pyrimidine EGFR inhibitor by screening an irreversible kinase inhibitor library specifically against EGFR T790M. These agents are 30- to 100-fold more potentmore » against EGFR T790M, and up to 100-fold less potent against wild-type EGFR, than quinazoline-based EGFR inhibitors in vitro. They are also effective in murine models of lung cancer driven by EGFR T790M. Co-crystallization studies reveal a structural basis for the increased potency and mutant selectivity of these agents. These mutant-selective irreversible EGFR kinase inhibitors may be clinically more effective and better tolerated than quinazoline-based inhibitors. Our findings demonstrate that functional pharmacological screens against clinically important mutant kinases represent a powerful strategy to identify new classes of mutant-selective kinase inhibitors.« less

Design, synthesis, antiviral bioactivity and three-dimensional quantitative structure-activity relationship study of novel ferulic acid ester derivatives containing quinazoline moiety.

PubMed

Wu, Zengxue; Zhang, Jian; Chen, Jixiang; Pan, Jianke; Zhao, Lei; Liu, Dengyue; Zhang, Awei; Chen, Jin; Hu, Deyu; Song, Baoan

2017-10-01

Ferulic acid and quinazoline derivatives possess good antiviral activities. In order to develop novel compounds with high antiviral activities, a series of ferulic acid ester derivatives containing quinazoline were synthesized and evaluated for their antiviral activities. Bioassays indicated that some of the compounds exhibited good antiviral activities in vivo against tobacco mosaic virus (TMV) and cucumber mosaic virus (CMV). One of the compounds demonstrated significant curative and protective activities against TMV and CMV, with EC 50 values of 162.14, 114.61 and 255.49, 138.81 mg L -1 , respectively, better than those of ningnanmycin (324.51, 168.84 and 373.88, 272.70 mg L -1 ). The values of q 2 and r 2 for comparative molecular field analysis and comparative molecular similarity index analysis in the TMV (0.508, 0.663 and 0.992, 0.930) and CMV (0.530, 0.626 and 0.997, 0.981) models presented good predictive abilities. Some of the title compounds demonstrated good antiviral activities. Three-dimensional quantitative structure-activity relationship models revealed that the antiviral activities depend on steric and electrostatic properties. These results could provide significant structural insights for the design of highly active ferulic acid derivatives. © 2017 Society of Chemical Industry. © 2017 Society of Chemical Industry.

Synthesis of Novel Derivatives of Quinazoline Schiff base Compound Promotes Epithelial Wound Healing.

PubMed

Bagheri, Elham; Saremi, Kamelia; Hajiaghaalipour, Fatemeh; Faraj, Fadhil Lafta; Ali, Hapipah Mohd; Abdulla, Mahmood Ameen; Khaing, Si Lay; Salehen, Nur'Ain

2018-01-30

Quinazoline is an aromatic bicyclic compound exhibiting several pharmaceutical and biological activities. This study was conducted to investigate the potential wound healing properties of synthetic quinazoline compound (SQC) on experimental rats. The toxicity of SQC was determined by MTT cell proliferation assay. The healing effect of SQC was assessed by in vitro wound healing scratch assay on the skin fibroblast cells (BJ-5ta) and in vivo wound healing experiment of low and high dose of SQC on adult Sprague-Dawley rats compared with negative (gum acacia) and positive control (Intrasite-gel). Hematoxylin and eosin (H&E), Masson's trichrome (MT) staining and immunohistochemistry analysis were performed to evaluate the histopathological alterations and proteins expression of Bax and Hsp70 on the wound tissue after 10 days. In addition, levels of antioxidant enzymes (catalase, glutathione peroxidase and superoxide dismutase), and malondialdehyde (MDA) were measured in wound tissue homogenates. The SQC significantly enhanced BJ-5ta cell proliferation and accelerated the percentage of wound closure, with less scarring, increased fibroblast and collagen fibers and less inflammatory cells compared with the negative control. The compound also increases endogenous enzymes and decline lipid peroxidation in wound homogenate. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

QSAR-Based Models for Designing Quinazoline/Imidazothiazoles/Pyrazolopyrimidines Based Inhibitors against Wild and Mutant EGFR

PubMed Central

Chauhan, Jagat Singh; Dhanda, Sandeep Kumar; Singla, Deepak; Agarwal, Subhash M.; Raghava, Gajendra P. S.

2014-01-01

Overexpression of EGFR is responsible for causing a number of cancers, including lung cancer as it activates various downstream signaling pathways. Thus, it is important to control EGFR function in order to treat the cancer patients. It is well established that inhibiting ATP binding within the EGFR kinase domain regulates its function. The existing quinazoline derivative based drugs used for treating lung cancer that inhibits the wild type of EGFR. In this study, we have made a systematic attempt to develop QSAR models for designing quinazoline derivatives that could inhibit wild EGFR and imidazothiazoles/pyrazolopyrimidines derivatives against mutant EGFR. In this study, three types of prediction methods have been developed to design inhibitors against EGFR (wild, mutant and both). First, we developed models for predicting inhibitors against wild type EGFR by training and testing on dataset containing 128 quinazoline based inhibitors. This dataset was divided into two subsets called wild_train and wild_valid containing 103 and 25 inhibitors respectively. The models were trained and tested on wild_train dataset while performance was evaluated on the wild_valid called validation dataset. We achieved a maximum correlation between predicted and experimentally determined inhibition (IC50) of 0.90 on validation dataset. Secondly, we developed models for predicting inhibitors against mutant EGFR (L858R) on mutant_train, and mutant_valid dataset and achieved a maximum correlation between 0.834 to 0.850 on these datasets. Finally, an integrated hybrid model has been developed on a dataset containing wild and mutant inhibitors and got maximum correlation between 0.761 to 0.850 on different datasets. In order to promote open source drug discovery, we developed a webserver for designing inhibitors against wild and mutant EGFR along with providing standalone (http://osddlinux.osdd.net/) and Galaxy (http://osddlinux.osdd.net:8001) version of software. We hope our webserver (http://crdd.osdd.net/oscadd/ntegfr/) will play a vital role in designing new anticancer drugs. PMID:24992720

Polymyxins and quinazolines are LSD1/KDM1A inhibitors with unusual structural features.

PubMed

Speranzini, Valentina; Rotili, Dante; Ciossani, Giuseppe; Pilotto, Simona; Marrocco, Biagina; Forgione, Mariantonietta; Lucidi, Alessia; Forneris, Federico; Mehdipour, Parinaz; Velankar, Sameer; Mai, Antonello; Mattevi, Andrea

2016-09-01

Because of its involvement in the progression of several malignant tumors, the histone lysine-specific demethylase 1 (LSD1) has become a prominent drug target in modern medicinal chemistry research. We report on the discovery of two classes of noncovalent inhibitors displaying unique structural features. The antibiotics polymyxins bind at the entrance of the substrate cleft, where their highly charged cyclic moiety interacts with a cluster of positively charged amino acids. The same site is occupied by quinazoline-based compounds, which were found to inhibit the enzyme through a most peculiar mode because they form a pile of five to seven molecules that obstruct access to the active center. These data significantly indicate unpredictable strategies for the development of epigenetic inhibitors.

Recent advances in the structural library of functionalized quinazoline and quinazolinone scaffolds: synthetic approaches and multifarious applications.

PubMed

Khan, Imtiaz; Ibrar, Aliya; Abbas, Naeem; Saeed, Aamer

2014-04-09

Drug development has been a principal driving force in the rapid maturation of the field of medicinal chemistry during the past several decades. During this period, the intriguing and challenging molecular architectures of nitrogen-containing heterocycles with potential bioactive properties have received significant attention from researchers engaged in the areas of natural product synthesis and heterocyclic methodology, and constituted a continuous stimulus for development in bio(organic) chemistry. In this perspective, the current review article is an effort to summarize recent developments in the environmentally benign synthetic methods providing access to quinazoline and quinazolinone scaffolds with promising biological potential. This article also aims to discuss potential future directions on the development of more potent and specific analogues for various biological targets. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Synthesis of novel quinazolin-4(3H)-one derivatives containing the 7-oxo-1,2,4-triazolo[1,5-a]pyrimidine moiety as effective agricultural bactericides against the pathogen Xanthomonas oryzae pv. oryzae.

PubMed

Du, Huan; Fan, Zhijiang; Yang, Lan; Bao, Xiaoping

2018-02-01

A series of novel quinazolin-4-one derivatives (7a-7n) bearing the 7-oxo-1,2,4-triazolo[1,5-a]pyrimidine moiety were designed, synthesized and evaluated for their inhibition activities against phytopathogenic bacteria and fungi in vitro. All of the target compounds were fully characterized through [Formula: see text] NMR, [Formula: see text] NMR, HRMS and IR spectra. Among these compounds, the structure of compound 7e was unambiguously confirmed via single-crystal X-ray diffraction analysis. The turbidimetric assays indicated that compounds 7b, 7d, 7g, 7k and 7n exhibited much more potent inhibition activities against the pathogen Xanthomonas oryzae pv. oryzae (Xoo), relative to control Bismerthiazol. Moreover, antibacterial activities of compounds 7j, 7k and 7n against the pathogen Xanthomonas axonopodis pv. citri (Xac) were comparable to that of control Bismerthiazol. As for the pathogen Ralstonia solanacearum (Rs), only compounds 7g and 7i demonstrated inhibition activities similar to control Thiadiazole-copper. Moreover, this class of compounds did not display inhibition activity against three fungi tested. The above findings indicated that quinazolin-4-one derivatives containing the 7-oxo-1,2,4-triazolo[1,5-a]pyrimidine moiety have a potential as promising candidates for the development of new and more efficient agricultural bactericides.

Quinazoline derivative from indigenous isolate, Nocardiopsis alba inhibits human telomerase enzyme.

PubMed

Kiran, K G; Thandeeswaran, M; Ayub Nawaz, K A; Easwaran, M; Jayagopi, K K; Ebrahimi, L; Palaniswamy, M; Mahendran, R; Angayarkanni, J

2016-12-01

Aim of this study was isolation and screening of various secondary metabolites produced by indigenous isolates of soil Actinomycetes for human telomerase inhibitory activity. Extracellular extract from culture suspension of various soil Actinomycetes species were tested for telomerase inhibitory activity. The organism which produced telomerase inhibitor was identified by 16S rRNA gene sequencing. The active fraction was purified by HPLC and analysed by GC-MS to identify the compound. In GC-MS analysis, the active principle was identified as 3-[4'-(2″-chlorophenyl)-2'-thiazolyl]-2,4-dioxo-1,2,3,4-tetrahydro quinazoline. The G-quadruplex stabilizing ability of the compound was checked by molecular docking and simulation experiments with G-quadruplex model (PDB ID-1L1H). The selective binding ability of the compound with G-quadruplex over Dickerson-Drew dodecamer DNA structures showed that the compound possess high selectivity towards G-quadruplex. Quinazoline derivative isolated from an indigenous strain of Nocardiopsis alba inhibited telomerase. Molecular docking and simulation studies predicted that this compound is a strong stabilizer of G-quadruplex conformation. It also showed a preferable binding to G-quadruplex DNA over normal DNA duplex. This particular compound can be suggested as a suitable compound for developing a future anticancer drug. The selectivity towards G-quadruplex over normal DNA duplex gives a clue that it is likely to show lower cytotoxicity in normal cells. © 2016 The Society for Applied Microbiology.

A Palladium-Catalyzed Method for the Synthesis of 2-(α-Styryl)-2,3-dihydroquinazolin-4-ones and 3-(α-Styryl)-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide: Access to 2-(α-Styryl)quinazolin-4(3H)-ones and 3-(α-Styryl)-1,2,4-benzothiadiazine-1,1-dioxides.

PubMed

Kundu, Priyanka; Mondal, Amrita; Chowdhury, Chinmay

2016-08-05

An efficient synthesis of 2-(α-styryl)-2,3-dihydroquinazolin-4-ones and 3-(α-styryl)-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxides has been achieved in 39-94% yield through palladium-catalyzed cyclocondensation of aryl/vinyl iodides with allenamides 13-15 and 22, respectively. Base treatment of the N-tosylated products provides an easy access to 2-(α-styryl)quinazolin-4(3H)-ones and 3-(α-styryl)-1,2,4-benzothiadiazine-1,1-dioxides, hitherto unknown heterocycles. The method has been tested with phenyl substituted allenamides, applied for bis-heteroannulation, and used in the preparation of analogues of the natural product Luotonin F.

Discovery of novel quinazoline-2,4(1H,3H)-dione derivatives as potent PARP-2 selective inhibitors.

PubMed

Zhao, Hailong; Ji, Ming; Cui, Guonan; Zhou, Jie; Lai, Fangfang; Chen, Xiaoguang; Xu, Bailing

2017-08-01

The PARP-2 selective inhibitor is important for clarifying specific roles of PARP-2 in the pathophysiological process and developing desired drugs with reduced off-target side effects. In this work, a series of novel quinazoline-2,4(1H,3H)-dione derivatives was designed and synthesized to explore isoform selective PARP inhibitors. As a result, compound 11a (PARP-1 IC 50 =467nM, PARP-2 IC 50 =11.5nM, selectivity PARP-1/PARP-2=40.6) was disclosed as the most selective PARP-2 inhibitor with high potency to date. The binding features of compound 11a within PARP-1 and PARP-2 were investigated respectively to provide useful insights for the further construction of new isoform selective inhibitors of PARP-1 and PARP-2 by using CDOCKER program. Copyright © 2017 Elsevier Ltd. All rights reserved.

Quinazoline clubbed 1,3,5-triazine derivatives as VEGFR2 kinase inhibitors: design, synthesis, docking, in vitro cytotoxicity and in ovo antiangiogenic activity.

PubMed

Pathak, Prateek; Shukla, Parjanya Kumar; Kumar, Vikas; Kumar, Ankit; Verma, Amita

2018-04-16

A series of quinazoline clubbed 1,3,5-triazine derivatives (QCT) were synthesized and evaluated for their in vitro anticancer activity against HeLa (human cervical cancer), MCF-7 (human breast cancer cell), HL-60 (human promyelocytic leukemia cell), HepG2 (human Hepatocellular carcinoma cell), and one normal cell line HFF (human foreskin fibroblasts). In vitro assay result encouraged to further move towards in ovo anticancer evaluation using chick embryo. The series of QCT derivatives showed higher anticancer and antiangiogenic activity against HeLa and MCF-7 cell lines. In the series, synthetic molecule 8d, 8l, and 8m displayed significant activity. Further, these results substantiated by docking study on VGFR2. SAR study concluded that the potency of drugs depends on the nature of aliphatic substitution and the heterocyclic ring system.

Optimization of 2-Anilino 4-Amino Substituted Quinazolines into Potent Antimalarial Agents with Oral in Vivo Activity.

PubMed

Gilson, Paul R; Tan, Cyrus; Jarman, Kate E; Lowes, Kym N; Curtis, Joan M; Nguyen, William; Di Rago, Adrian E; Bullen, Hayley E; Prinz, Boris; Duffy, Sandra; Baell, Jonathan B; Hutton, Craig A; Jousset Subroux, Helene; Crabb, Brendan S; Avery, Vicky M; Cowman, Alan F; Sleebs, Brad E

2017-02-09

Novel antimalarial therapeutics that target multiple stages of the parasite lifecycle are urgently required to tackle the emerging problem of resistance with current drugs. Here, we describe the optimization of the 2-anilino quinazoline class as antimalarial agents. The class, identified from publicly available antimalarial screening data, was optimized to generate lead compounds that possess potent antimalarial activity against P. falciparum parasites comparable to the known antimalarials, chloroquine and mefloquine. During the optimization process, we defined the functionality necessary for activity and improved in vitro metabolism and solubility. The resultant lead compounds possess potent activity against a multidrug resistant strain of P. falciparum and arrest parasites at the ring phase of the asexual stage and also gametocytogensis. Finally, we show that the lead compounds are orally efficacious in a 4 day murine model of malaria disease burden.

2-Guanidino-quinazolines as a novel class of translation inhibitors.

PubMed

Komarova Andreyanova, E S; Osterman, I A; Pletnev, P I; Ivanenkov, Y A; Majouga, A G; Bogdanov, A A; Sergiev, P V

2017-02-01

A variety of structurally unrelated organic compounds has been reported to have antibacterial activity. Among these, certain small-molecule translation inhibitors have attracted a great deal of attention, due to their relatively high selectivity against prokaryotes, and an appropriate therapeutic index with minor "off target" effects. However, ribosomes are being considered as poorly druggable biological targets, thereby making some routine computational-based approaches to rational drug design and its development rather ineffective. Taking this into account, diversity-oriented biological screening can reasonably be considered as the most advantageous strategy. Thus, using a high-throughput screening (HTS) platform, we applied a unique biological assay for in vitro evaluation of thousands of organic molecules, especially targeted against bacterial ribosomes and translation. As a result, we have identified a series of structurally diverse small-molecule compounds that induce a reporter strain sensitive to translation and DNA biosynthesis inhibitors. In a cell free system, several molecules were found to strongly inhibit protein biosynthesis. Among them, compounds bearing a 2-guanidino-quinazoline core demonstrated the most promising antibacterial activity. With regard to the preliminary structure-activity relationship (SAR) study, we revealed that relatively small substituents at positions 4, 6 and 8 of the quinazoline ring significantly enhance the target activity whereas modification of the guanidine group leads to decrease or loss of antibacterial potency. This novel class of translation inhibitors can properly be regarded as a promising starting point for the development of novel antibacterial therapeutic or screening tools. Copyright © 2016 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.

In Vitro and In Vivo Metabolism and Inhibitory Activities of Vasicine, a Potent Acetylcholinesterase and Butyrylcholinesterase Inhibitor

PubMed Central

Liu, Wei; Shi, Xiaoyuan; Yang, Yadi; Cheng, Xuemei; Liu, Qing; Han, Han; Yang, Baohua; He, Chunyong; Wang, Yongli; Jiang, Bo; Wang, Zhengtao; Wang, Changhong

2015-01-01

Vasicine (VAS), a potential natural cholinesterase inhibitor, exhibited promising anticholinesterase activity in preclinical models and has been in development for treatment of Alzheimer’s disease. This study systematically investigated the in vitro and in vivo metabolism of VAS in rat using ultra performance liquid chromatography combined with electrospray ionization quadrupole time-of-flight mass spectrometry. A total of 72 metabolites were found based on a detailed analysis of their 1H- NMR and 13C NMR data. Six key metabolites were isolated from rat urine and elucidated as vasicinone, vasicinol, vasicinolone, 1,2,3,9-tetrahydropyrrolo [2,1-b] quinazolin-3-yl hydrogen sulfate, 9-oxo-1,2,3,9-tetrahydropyrrolo [2,1-b] quinazolin-3-yl hydrogen sulfate, and 1,2,3,9-tetrahydropyrrolo [2,1-b] quinazolin-3-β-D-glucuronide. The metabolic pathway of VAS in vivo and in vitro mainly involved monohydroxylation, dihydroxylation, trihydroxylation, oxidation, desaturation, sulfation, and glucuronidation. The main metabolic soft spots in the chemical structure of VAS were the 3-hydroxyl group and the C-9 site. All 72 metabolites were found in the urine sample, and 15, 25, 45, 18, and 11 metabolites were identified from rat feces, plasma, bile, rat liver microsomes, and rat primary hepatocyte incubations, respectively. Results indicated that renal clearance was the major excretion pathway of VAS. The acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities of VAS and its main metabolites were also evaluated. The results indicated that although most metabolites maintained potential inhibitory activity against AChE and BChE, but weaker than that of VAS. VAS undergoes metabolic inactivation process in vivo in respect to cholinesterase inhibitory activity. PMID:25849329

[Design, synthesis and biological evaluation of novel para-substituted 1-benzyl-quinazoline-2, 4 (1H, 3H)-diones as human PARP-1 inhibitors].

PubMed

Yao, Hai-Ping; Zhu, Zhi-Xiang; Ji, Ming; Chen, Xiao-Guang; Xu, Bai-Ling

2014-04-01

Poly(ADP-ribose) polymerase-1 (PARP-1) has emerged as a promising anticancer drug target due to its key role in the DNA repair process. It can polymerize ADP-ribose units on its substrate proteins which are involved in the regulation of DNA repair. In this work, a novel series of para-substituted 1-benzyl-quinazoline-2, 4 (1H, 3H)-diones was designed and synthesized, and the inhibitory activities against PARP-1 of compounds 7a-7e, 8a-8f, 9a-9c and 10a-10c were evaluated. Of all the tested compounds, nine compounds displayed inhibitory activities with IC50 values ranging from 4.6 to 39.2 micromol x L(-1). In order to predict the binding modes of the potent molecules, molecular docking was performed using CDOCKER algorithm, and that will facilitate to further develop more potent PARP-1 inhibitors with a quinazolinedione scaffold.

QUANTUM MECHANICAL STUDY OF THE COMPETITIVE HYDRATION BETWEEN PROTONATED QUINAZOLINE AND LI+, NA+, AND CA2+ IONS

EPA Science Inventory

Hydration reactions are fundamental to many biological functions and environmental processes. The energetics of hydration of inorganic and organic chemical species influences their fate and transport behavior in the environment. In this study, gas-phase quantum mechanical calcula...

Identification and characterization of amino-piperidinequinolones and quinazolinones as MCHr1 antagonists.

PubMed

Blackburn, Christopher; LaMarche, Matthew J; Brown, James; Che, Jennifer Lee; Cullis, Courtney A; Lai, Sujen; Maguire, Martin; Marsilje, Thomas; Geddes, Bradley; Govek, Elizabeth; Kadambi, Vivek; Doherty, Colleen; Dayton, Brian; Brodjian, Sevan; Marsh, Kennan C; Collins, Christine A; Kym, Philip R

2006-05-15

Several potent, functionally active MCHr1 antagonists derived from quinolin-2(1H)-ones and quinazoline-2(1H)-ones have been synthesized and evaluated. Pyridylmethyl substitution at the quinolone 1-position results in derivatives with low-nM binding potency and good selectivity with respect to hERG binding.

Molecular Modeling Studies of 4,5-Dihydro-1H-pyrazolo[4,3-h] quinazoline Derivatives as Potent CDK2/Cyclin A Inhibitors Using 3D-QSAR and Docking

PubMed Central

Ai, Yong; Wang, Shao-Teng; Sun, Ping-Hua; Song, Fa-Jun

2010-01-01

CDK2/cyclin A has appeared as an attractive drug targets over the years with diverse therapeutic potentials. A computational strategy based on comparative molecular fields analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) followed by molecular docking studies were performed on a series of 4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline derivatives as potent CDK2/cyclin A inhibitors. The CoMFA and CoMSIA models, using 38 molecules in the training set, gave r2cv values of 0.747 and 0.518 and r2 values of 0.970 and 0.934, respectively. 3D contour maps generated by the CoMFA and CoMSIA models were used to identify the key structural requirements responsible for the biological activity. Molecular docking was applied to explore the binding mode between the ligands and the receptor. The information obtained from molecular modeling studies may be helpful to design novel inhibitors of CDK2/cyclin A with desired activity. PMID:21152296

La(III) complex involving the O,N-donor environment of quinazoline-4(3H)-one Schiff’s base and their antimicrobial attributes against methicillin-resistant Staphylococcus aureus (MRSA)

NASA Astrophysics Data System (ADS)

Siddappa, K.; Mane, Sunilkumar B.; Manikprabhu, Deene

2014-09-01

The incidence of methicillin-resistant Staphylococcus aureus increased during the past few decades, so there is an urgent need of new antimicrobial agents if public health is concerned. Though the Schiff’s bases and La(III) complex have enormous biological activity, but less attention was given in their synthesis. In the present investigation, we synthesized a new (E)-3-((2-hydroxynaphthalen-1-yl) methyleneamino)-2-methylquinazoline-4(3H)-one HNMAMQ Schiff’s base by the condensation of 3-(2-aminophenyl) quinazolin-2-methyl-4(3H)-one and 2-hydroxy-1-naphthaldehyde. The Schiff’s base HNMAMQ and its La(III) complex were characterized by elemental analyses, IR, NMR, mass spectra, and thermal studies. The newly synthesized Schiff’s base HNMAMQ and its La(III) complex were evaluated for their antimicrobial activity against methicillin-resistant Staphylococcus aureus isolated from the Gulbarga region in India. The Schiff’s base HNMAMQ and its La(III) complex showed good antimicrobial activity and thus represents a potential new drug of choice.

Discovery of 2-(2-aminopyrimidin-5-yl)-4-morpholino-N-(pyridin-3-yl)quinazolin-7-amines as novel PI3K/mTOR inhibitors and anticancer agents.

PubMed

Peng, Wei; Tu, Zheng-Chao; Long, Zi-Jie; Liu, Quentin; Lu, Gui

2016-01-27

In this study, a series of novel 7 or 8-substituted 4-morpholine-quinazoline derivatives was designed and synthesized. Their PI3Kα inhibitory activities, antiproliferative activities against seven cancer cell lines, namely, PC-3, DU145, MCF-7, BT474, SK-BR-3, U937 and A431, were evaluated in vitro. Compound 17f proved to be a potential drug candidate with high PI3Kα inhibition activity (IC50 = 4.2 nM) and good antiproliferative activity. Compound 17f was also tested for its inhibitory activities against other kinases, such as PI3Kβ, PI3Kγ, PI3Kδ and mTOR, its effects on p-Akt (S473) and cell cycle. These results suggested that compound 17f could significantly inhibit the PI3K/Akt/mTOR pathway as a potent PI3K inhibitor and anticancer agent. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Molecular modeling studies of 4,5-dihydro-1H-pyrazolo[4,3-h] quinazoline derivatives as potent CDK2/Cyclin a inhibitors using 3D-QSAR and docking.

PubMed

Ai, Yong; Wang, Shao-Teng; Sun, Ping-Hua; Song, Fa-Jun

2010-09-28

CDK2/cyclin A has appeared as an attractive drug targets over the years with diverse therapeutic potentials. A computational strategy based on comparative molecular fields analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) followed by molecular docking studies were performed on a series of 4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline derivatives as potent CDK2/cyclin A inhibitors. The CoMFA and CoMSIA models, using 38 molecules in the training set, gave r(2) (cv) values of 0.747 and 0.518 and r(2) values of 0.970 and 0.934, respectively. 3D contour maps generated by the CoMFA and CoMSIA models were used to identify the key structural requirements responsible for the biological activity. Molecular docking was applied to explore the binding mode between the ligands and the receptor. The information obtained from molecular modeling studies may be helpful to design novel inhibitors of CDK2/cyclin A with desired activity.

Study of antileishmanial activity of 2-aminobenzoyl amino acid hydrazides and their quinazoline derivatives.

PubMed

Khattab, Sherine Nabil; Haiba, Nesreen Saied; Asal, Ahmed Mosaad; Bekhit, Adnan A; Guemei, Aida A; Amer, Adel; El-Faham, Ayman

2017-02-15

A new small library of 2-aminobenzoyl amino acid hydrazide derivatives and quinazolinones derivatives was synthesized and fully characterized by IR, NMR, and elemental analysis. The activity of the prepared compounds on the growth of Leishmania aethiopica promastigotes was evaluated. 2-Benzoyl amino acid hydrazide showed higher inhibitory effect than the quinazoline counterpart. The in vitro antipromastigote activity demonstrated that compounds 2a, 2b, 2f and 4a had IC 50 better than standard drug miltefosine and comparable activity to amphotericin B deoxycholate, which indicates their high antileishmanial activity against Leishmania. aethiopica. Among the prepared compounds; 2-amino-N-(6-hydrazinyl-6-oxohexyl)benzamide 2f (IC 50 =0.051μM) has the best activity, 154 folds more active than reference standard drug miltefosine (IC 50 =7.832μM), and half fold the activity of amphotericin B (IC 50 =0.035μM). In addition, this compound was safe and well tolerated by experimental animals orally up to 250mg/kg and parenterally up to 100mg/kg. Copyright © 2017 Elsevier Ltd. All rights reserved.

Discovery and SAR of Novel 2,3‐Dihydroimidazo[1,2‐c]quinazoline PI3K Inhibitors: Identification of Copanlisib (BAY 80‐6946)

PubMed Central

Hentemann, Martin F.; Rowley, R. Bruce; Bull, Cathy O.; Jenkins, Susan; Bullion, Ann M.; Johnson, Jeffrey; Redman, Anikó; Robbins, Arthur H.; Esler, William; Fracasso, R. Paul; Garrison, Timothy; Hamilton, Mark; Michels, Martin; Wood, Jill E.; Wilkie, Dean P.; Xiao, Hong; Levy, Joan; Stasik, Enrico; Liu, Ningshu; Schaefer, Martina; Brands, Michael

2016-01-01

Abstract The phosphoinositide 3‐kinase (PI3K) pathway is aberrantly activated in many disease states, including tumor cells, either by growth factor receptor tyrosine kinases or by the genetic mutation and amplification of key pathway components. A variety of PI3K isoforms play differential roles in cancers. As such, the development of PI3K inhibitors from novel compound classes should lead to differential pharmacological and pharmacokinetic profiles and allow exploration in various indications, combinations, and dosing regimens. A screening effort aimed at the identification of PI3Kγ inhibitors for the treatment of inflammatory diseases led to the discovery of the novel 2,3‐dihydroimidazo[1,2‐c]quinazoline class of PI3K inhibitors. A subsequent lead optimization program targeting cancer therapy focused on inhibition of PI3Kα and PI3Kβ. Herein, initial structure–activity relationship findings for this class and the optimization that led to the identification of copanlisib (BAY 80‐6946) as a clinical candidate for the treatment of solid and hematological tumors are described. PMID:27310202

Design, synthesis, antiproliferative activity and docking studies of quinazoline derivatives bearing 2,3-dihydro-indole or 1,2,3,4-tetrahydroquinoline as potential EGFR inhibitors.

PubMed

OuYang, Yiqiang; Zou, Wensheng; Peng, Liang; Yang, Zunhua; Tang, Qidong; Chen, Mengzi; Jia, Shuang; Zhang, Hong; Lan, Zhou; Zheng, Pengwu; Zhu, Wufu

2018-05-09

Eight series of quinazoline derivatives bearing 2,3-dihydro-indole or 1,2,3,4-tetrahydroquinoline were designed, synthesized and evaluated for the IC 50 values against three cancer cell lines (A549, MCF-7 and PC-3). Most of the forty nine target compounds showed excellent antiproliferative activity against one or several cancer cell lines. The compound 13a showed the best activity against A549, MCF-7 and PC-3 cancer cell lines, with the IC 50 values of 1.09 ± 0.04 μM, 1.34 ± 0.13 μM and 1.23 ± 0.09 μM, respectively. Eight selected compounds were further selected to evaluated for the inhibitory activity against EGFR kinase. Three of them showed equal activity against EGFR kinase to positive control afatinib. AnnexinV-FITC, propidium iodide (PI) double staining and acridine orange single staining results indicated that the compound 13a could induce apoptosis of human lung cancer A549 cells. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Profiling the interaction mechanism of quinoline/quinazoline derivatives as MCHR1 antagonists: an in silico method.

PubMed

Wu, Mingwei; Li, Yan; Fu, Xinmei; Wang, Jinghui; Zhang, Shuwei; Yang, Ling

2014-09-01

Melanin concentrating hormone receptor 1 (MCHR1), a crucial regulator of energy homeostasis involved in the control of feeding and energy metabolism, is a promising target for treatment of obesity. In the present work, the up-to-date largest set of 181 quinoline/quinazoline derivatives as MCHR1 antagonists was subjected to both ligand- and receptor-based three-dimensional quantitative structure-activity (3D-QSAR) analysis applying comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). The optimal predictable CoMSIA model exhibited significant validity with the cross-validated correlation coefficient (Q²) = 0.509, non-cross-validated correlation coefficient (R²(ncv)) = 0.841 and the predicted correlation coefficient (R²(pred)) = 0.745. In addition, docking studies and molecular dynamics (MD) simulations were carried out for further elucidation of the binding modes of MCHR1 antagonists. MD simulations in both water and lipid bilayer systems were performed. We hope that the obtained models and information may help to provide an insight into the interaction mechanism of MCHR1 antagonists and facilitate the design and optimization of novel antagonists as anti-obesity agents.

New stereoselective intramolecular

PubMed

Alajarin; Vidal; Tovar; Ramirez De Arellano MC; Cossio; Arrieta; Lecea

2000-11-03

Efficient 1,4-asymmetric induction has been achieved in the highly stereocontrolled intramolecular [2 + 2] cycloadditions between ketenimines and imines, leading to 1,2-dihydroazeto[2, 1-b]quinazolines. The chiral methine carbon adjacent to the iminic nitrogen controls the exclusive formation of the cycloadducts with relative trans configuration at C2 and C8. The stepwise mechanistic model, based on theoretical calculations, fully supports the stereochemical outcome of these cycloadditions.

p-TSA-promoted syntheses of 5H-benzo[h] thiazolo[2,3-b]quinazoline and indeno[1,2-d] thiazolo[3,2-a]pyrimidine analogs: molecular modeling and in vitro antitumor activity against hepatocellular carcinoma.

PubMed

Keshari, Amit K; Singh, Ashok K; Raj, Vinit; Rai, Amit; Trivedi, Prakruti; Ghosh, Balaram; Kumar, Umesh; Rawat, Atul; Kumar, Dinesh; Saha, Sudipta

2017-01-01

In our efforts to address the rising incidence of hepatocellular carcinoma (HCC), we have made a commitment to the synthesis of novel molecules to combat Hep-G2 cells. A facile and highly efficient one-pot, multicomponent reaction has been successfully devised utilizing a p -toluenesulfonic acid ( p -TSA)-catalyzed domino Knoevenagel/Michael/intramolecular cyclization approach for the synthesis of novel 5H-benzo[h]thiazolo[2,3-b]quinazoline and indeno[1,2-d] thiazolo[3,2-a]pyrimidine analogs bearing a bridgehead nitrogen atom. This domino protocol constructed one new ring by the concomitant formation of multiple bonds (C-C, C-N, and C=N) involving multiple steps without the use of any metal catalysts in one-pot, with all reactants effi-ciently exploited. All the newly synthesized compounds were authenticated by means of Fourier transform infrared spectroscopy, liquid chromatography-mass spectrometry, proton nuclear magnetic resonance spectroscopy, and carbon-13 nuclear magnetic resonance spectroscopy, together with elemental analysis, and their antitumor activity was evaluated in vitro on a Hep-G2 human cancer cell line by sulforhodamine B assay. Computational molecular modeling studies were carried out on cancer-related targets, including interleukin-2, interleukin-6, Caspase-3, and Caspase-8. Two compounds (4A and 6A) showed growth inhibitory activity comparable to the positive control Adriamycin, with growth inhibition of 50% <10 μg/mL. The results of the comprehensive structure-activity relationship study confirmed the assumption that two or more electronegative groups on the phenyl ring attached to the thiazolo[2,3-b]quinazoline system showed the optimum effect. The in silico simulations suggested crucial hydrogen bond and π-π stacking interactions, with a good ADMET (absorption, distribution, metabolism, excretion, and toxicity) profile and molecular dynamics, in order to explore the molecular targets of HCC which were in complete agreement with the in vitro findings. Considering their significant anticancer activity, 4A and 6A are potential drug candidates for the management of HCC.

Discovery of potent and selective cytotoxic activity of new quinazoline-ureas against TMZ-resistant glioblastoma multiforme (GBM).

PubMed

Elkamhawy, Ahmed; Viswanath, Ambily Nath Indu; Pae, Ae Nim; Kim, Hyeon Young; Heo, Jin-Chul; Park, Woo-Kyu; Lee, Chong-Ock; Yang, Heekyoung; Kim, Kang Ho; Nam, Do-Hyun; Seol, Ho Jun; Cho, Heeyeong; Roh, Eun Joo

2015-10-20

Herein, we report new quinazoline-urea based compounds with potent cytotoxic activities against TMZ-resistant glioblastoma multiforme (GBM) cells. Low micromolar IC₅₀ values were exhibited over a panel of three primary GBM patient-derived cell cultures belonging to proneural (GBM-1), mesenchymal (GBM-2), and classical (GBM-3) subtypes. Eight compounds showed excellent selectivity indices for GBM cells comparing to a normal astrocyte cell line. In JC-1 assay, analogues 11, 12, 20, 22, and 24 exerted promising rates of mPTP opening induction towards proneural GBM subtype. Compounds 11, 20, and 24 bound to the translocator protein 18 kDa (TSPO) in submicromolar range using [(3)H] PK-11195 binding affinity assay. A homology model was built and docked models of 11, 12, 20, 22 and 24 were generated for describing their plausible binding modes in TSPO. In 3D clonogenic assay, compound 20 manifested potent tumoricidal effects on TMZ-resistant GBM cells even at submicromolar concentrations. In addition, CYP450 and hERG assays presented a safe toxicity profile of 20. Taken as a whole, this report presents compound 20 as a potent, selective and safe GBM cytotoxic agent which constitutes a promising direction against TMZ-resistant GBM. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Synthesis, anti-microbial and molecular docking studies of quinazolin-4(3H)-one derivatives.

PubMed

Mabkhot, Yahia Nasser; Al-Har, Munirah S; Barakat, Assem; Aldawsari, Fahad D; Aldalbahi, Ali; Ul-Haq, Zaheer

2014-06-25

In this work, synthesis, antimicrobial activities and molecular docking studies of some new series of substituted quinazolinone 2a-h and 3a-d were described. Starting form 2-aminobenzamide derivatives 1, a new series of quinazolinone derivatives has been synthesized, in high yields, assisted by microwave and classical methods. Some of these substituted quinazolinones were tested for their antimicrobial activity against Gram-negative bacteria (Pseudomonas aeruginosa and Esherichia coli) and Gram-positive bacteria (Staphylococcus aureus, and Bacillus subtilis), and anti-fungal activity against (Aspergillus fumigatus, Saccharomyces cervevisiae, and Candida albicans) using agar well diffusion method. Among the prepared products, 3-benzyl-2-(4-chlorophenyl)quinazolin-4(3H)-one (3a) was found to exhibits the most potent in vitro anti-microbial activity with MICs of 25.6±0.5, 24.3±0.4, 30.1±0.6, and 25.1±0.5 µg/mL against Staphylococcus aureus, Bacillus subtilis, Pseudomonas aeruginosa and Esherichia coli, respectively. Compound 3a was found to exhibits the most potent in vitro anti-fungal activity with MICs of 18.3±0.6, 23.1±0.4, and 26.1±0.5 µg/mL against Aspergillus fumigatus, Saccharomyces cervevisiae, and Candidaal bicans, respectively.

Synthesis, antimicrobial evaluation and docking studies of some novel quinazolinone Schiff base derivatives

PubMed Central

Nasab, Rezvan Rezaee; Mansourian, Mahboubeh; Hassanzadeh, Farshid

2018-01-01

The quinazolin-4(3H)-one structural motif possesses a wide spectrum of biological activities. DNA gyrase play an important role in induction of bacterial death. It has been shown that many quinazolin-4(3H)-one derivatives have antibacterial effects through inhibition of DNA gyrase. Based on this information we decided to synthesize novel quinazolinone Schiff base derivatives in order to evaluate their antibacterial effects. A series of novel quinazolinone Schiff base derivatives were designed and synthesized from benzoic acid. The potential DNA gyrase inhibitory activity of these compounds was investigated using in silico molecular docking simulation. All new synthesized derivatives were screened for their antimicrobial activities against three species of Gram-negative bacteria including Escherichia coli, Pseudomonas aeruginosa, Salmonella entritidis and three species of Gram-positive bacteria comprising of Staphylococcus aurous, Bacillus subtilis, Listeria monocitogenes as well as for antifungal activities against Candida albicans using the conventional micro dilution method. Most of the compounds have shown good antibacterial activities, especially against E. coli at 128 µg/mL concentration while no remarkable antifungal activities were observed for these compounds. All the synthesized compounds exhibit dock score values between -5.96 and -8.58 kcal/mol. The highest dock score among them was -8.58 kcal/mol for compound 4c. PMID:29853931

N-(5-chloro-1,3-benzodioxol-4-yl)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5- (tetrahydro-2H-pyran-4-yloxy)quinazolin-4-amine, a novel, highly selective, orally available, dual-specific c-Src/Abl kinase inhibitor.

PubMed

Hennequin, Laurent F; Allen, Jack; Breed, Jason; Curwen, Jon; Fennell, Michael; Green, Tim P; Lambert-van der Brempt, Christine; Morgentin, Rémy; Norman, Richard A; Olivier, Annie; Otterbein, Ludovic; Plé, Patrick A; Warin, Nicolas; Costello, Gerard

2006-11-02

Src family kinases (SFKs) are nonreceptor tyrosine kinases that are reported to be critical for cancer progression. We report here a novel subseries of C-5-substituted anilinoquinazolines that display high affinity and specificity for the tyrosine kinase domain of the c-Src and Abl enzymes. These compounds exhibit high selectivity for SFKs over a panel of recombinant protein kinases, excellent pharmacokinetics, and in vivo activity following oral dosing. N-(5-Chloro-1,3-benzodioxol-4-yl)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5-(tetrahydro-2H-pyran-4-yloxy)quinazolin-4-amine (AZD0530) inhibits c-Src and Abl enzymes at low nanomolar concentrations and is highly selective over a range of kinases. AZD0530 displays excellent pharmacokinetic parameters in animal preclinically and in man (t(1/2) = 40 h). AZD0530 is a potent inhibitor of tumor growth in a c-Src-transfected 3T3-fibroblast xenograft model in vivo and led to a significant increase in survival in a highly aggressive, orthotopic model of human pancreatic cancer when dosed orally once daily. AZD0530 is currently undergoing clinical evaluation in man.

Synthesis, characterization, and anticancer activity of new quinazoline derivatives against MCF-7 cells.

PubMed

Faraj, Fadhil Lafta; Zahedifard, Maryam; Paydar, Mohammadjavad; Looi, Chung Yeng; Abdul Majid, Nazia; Ali, Hapipah Mohd; Ahmad, Noraini; Gwaram, Nura Suleiman; Abdulla, Mahmood Ameen

2014-01-01

Two new synthesized and characterized quinazoline Schiff bases 1 and 2 were investigated for anticancer activity against MCF-7 human breast cancer cell line. Compounds 1 and 2 demonstrated a remarkable antiproliferative effect, with an IC50 value of 6.246×10(-6) mol/L and 5.910×10(-6) mol/L, respectively, after 72 hours of treatment. Most apoptosis morphological features in treated MCF-7 cells were observed by AO/PI staining. The results of cell cycle analysis indicate that compounds did not induce S and M phase arrest in cell after 24 hours of treatment. Furthermore, MCF-7 cells treated with 1 and 2 subjected to apoptosis death, as exhibited by perturbation of mitochondrial membrane potential and cytochrome c release as well as increase in ROS formation. We also found activation of caspases-3/7, -8, and -9 in compounds 1 and 2. Moreover, inhibition of NF-κB translocation in MCF-7 cells treated by compound 1 significantly exhibited the association of extrinsic apoptosis pathway. Acute toxicity results demonstrated the nontoxic nature of the compounds in mice. Our results showed significant activity towards MCF-7 cells via either intrinsic or extrinsic mitochondrial pathway and are potential candidate for further in vivo and clinical breast cancer studies.

Synthesis, Characterization, and Anticancer Activity of New Quinazoline Derivatives against MCF-7 Cells

PubMed Central

Faraj, Fadhil Lafta; Zahedifard, Maryam; Paydar, Mohammadjavad; Looi, Chung Yeng; Abdul Majid, Nazia; Ali, Hapipah Mohd; Ahmad, Noraini; Gwaram, Nura Suleiman; Abdulla, Mahmood Ameen

2014-01-01

Two new synthesized and characterized quinazoline Schiff bases 1 and 2 were investigated for anticancer activity against MCF-7 human breast cancer cell line. Compounds 1 and 2 demonstrated a remarkable antiproliferative effect, with an IC50 value of 6.246 × 10−6 mol/L and 5.910 × 10−6 mol/L, respectively, after 72 hours of treatment. Most apoptosis morphological features in treated MCF-7 cells were observed by AO/PI staining. The results of cell cycle analysis indicate that compounds did not induce S and M phase arrest in cell after 24 hours of treatment. Furthermore, MCF-7 cells treated with 1 and 2 subjected to apoptosis death, as exhibited by perturbation of mitochondrial membrane potential and cytochrome c release as well as increase in ROS formation. We also found activation of caspases-3/7, -8, and -9 in compounds 1 and 2. Moreover, inhibition of NF-κB translocation in MCF-7 cells treated by compound 1 significantly exhibited the association of extrinsic apoptosis pathway. Acute toxicity results demonstrated the nontoxic nature of the compounds in mice. Our results showed significant activity towards MCF-7 cells via either intrinsic or extrinsic mitochondrial pathway and are potential candidate for further in vivo and clinical breast cancer studies. PMID:25548779

The DcpS inhibitor RG3039 improves motor function in SMA mice

PubMed Central

Van Meerbeke, James P.; Gibbs, Rebecca M.; Plasterer, Heather L.; Miao, Wenyan; Feng, Zhihua; Lin, Ming-Yi; Rucki, Agnieszka A.; Wee, Claribel D.; Xia, Bing; Sharma, Shefali; Jacques, Vincent; Li, Darrick K.; Pellizzoni, Livio; Rusche, James R.; Ko, Chien-Ping; Sumner, Charlotte J.

2013-01-01

Spinal muscular atrophy (SMA) is caused by mutations of the survival motor neuron 1 (SMN1) gene, retention of the survival motor neuron 2 (SMN2) gene and insufficient expression of full-length survival motor neuron (SMN) protein. Quinazolines increase SMN2 promoter activity and inhibit the ribonucleic acid scavenger enzyme DcpS. The quinazoline derivative RG3039 has advanced to early phase clinical trials. In preparation for efficacy studies in SMA patients, we investigated the effects of RG3039 in severe SMA mice. Here, we show that RG3039 distributed to central nervous system tissues where it robustly inhibited DcpS enzyme activity, but minimally activated SMN expression or the assembly of small nuclear ribonucleoproteins. Nonetheless, treated SMA mice showed a dose-dependent increase in survival, weight and motor function. This was associated with improved motor neuron somal and neuromuscular junction synaptic innervation and function and increased muscle size. RG3039 also enhanced survival of conditional SMA mice in which SMN had been genetically restored to motor neurons. As this systemically delivered drug may have therapeutic benefits that extend beyond motor neurons, it could act additively with SMN-restoring therapies delivered directly to the central nervous system such as antisense oligonucleotides or gene therapy. PMID:23727836

New Approaches for Prostate Cancer Combination Therapy

DTIC Science & Technology

2008-04-01

5 times whereas Finasteride , Diclofenac and Sulindac Sulfone 5 can be reduced 2 times when compared with the solvent controls, and still resulting...Flufenamic acid and Sulindac Sulfide; 20, 10, 5 and 2nM Flurbiprofen; 50, 25,10 and 5 µM Finasteride ; 200, 100,50 and 25 µM NS-398 and Sulindac...Diclofenac, Sulindac Sulfide, Finasteride and NS398 and NF-B inhibitors 6-Amino-4-(4-phenoxyphenylethylamino) quinazoline and IKK- 2 inhibitor SC-514

Synthesis and Antimicrobial Activity of 6-Thioxo-6,7-dihydro-2H-[1,2,4]triazino[2,3-c]-quinazolin-2-one Derivatives

PubMed Central

Nosulenko, Inna S.; Voskoboynik, Olexii Yu.; Berest, Galina G.; Safronyuk, Sergiy L.; Kovalenko, Sergiy I.; Kamyshnyi, Oleksandr M.; Polishchuk, Nataliya M.; Sinyak, Raisa S.; Katsev, Andrey V.

2014-01-01

Abstract Potassium 8-R1-9-R2-10-R3-3-R-2-oxo-2H-[1,2,4]triazino[2,3-c]quinazoline-6-thiolates 2.1–2.26 were synthesized via cyclocondensation of 6-R-3-(3-R1-4-R2-5-R3-aminophenyl)-1,2,4-triazin-5-ones 1.1–1.26 with carbon disulfide, potassium hydroxide, and ethanol or with potassium O-ethyl dithiocarbonate in 2-propanol. The corresponding thiones 3.1–3.26 were obtained by treatment of 2.1–2.26 with hydrochloric acid. It was found that the nature of the substituents in positions 3, 4, and 5 of the corresponding 6-R-3-(3-R1-4-R2-5-R3-aminophenyl)-1,2,4-triazin-5-ones were affected on the terms of the reaction. The structures of compounds were proven by a complex of physicochemical methods (1H, 13C NMR, LC–MS, and EI-MS). The results of the antibacterial and antifungal activity assay allowed the determination of the high sensitivity of Staphylococcus aureus ATCC 25923 (MIC 6.25–100 μg/mL, MBC 12.5–200 μg/mL) to the synthesized compounds. PMID:25853063

Development and Binding Mode Assessment of N-[4-[2-propyn-1-yl[(6S)-4,6,7,8-tetrahydro-2-(hydroxymethyl)-4-oxo-3H-cyclopenta[g]quinazolin-6-yl]amino]benzoyl]-L-γ-glutamyl-D-glutamic acid (BGC 945), a Novel Thymidylate Synthase Inhibitor that Targets Tumor Cells

PubMed Central

Tochowicz, Anna; Dalziel, Sean; Eidam, Oliv; O’Connell, Joseph D.; Griner, Sarah; Finer-Moore, Janet S.; Stroud, Robert M.

2013-01-01

N-[4-[2-propyn-1-yl[(6S)-4,6,7,8-tetrahydro-2-(hydroxymethyl)-4-oxo-3H-cyclopenta[g]quinazolin-6-yl]amino]benzoyl]-L-γ-glutamyl-D-glutamic acid 1 (BGC 945, now known as ONX 0801), is a small molecule thymidylate synthase (TS) inhibitor discovered at the Institute of Cancer Research in London. It is licensed by Onyx Pharmaceuticals and is in Phase 1 clinical studies. It is a novel antifolate drug resembling TS inhibitors plevitrexed and raltitrexed that combines enzymatic inhibition of thymidylate synthase with α-folate receptor-mediated targeting of tumor cells. Thus, it has potential for efficacy with lower toxicity due to selective intracellular accumulation through α-folate receptor (α-FR) transport. The α-FR, a cell-surface receptor glycoprotein, which is over expressed mainly in ovarian and lung cancer tumors, has an affinity for 1 similar to that for its natural ligand, folic acid. This study describes a novel synthesis of 1, an X-ray crystal structure of its complex with Escherichia coli TS and 2’-deoxyuridine-5’-monophosphate, and a model for a similar complex with human TS. PMID:23710599

A fragment-based approach applied to a highly flexible target: Insights and challenges towards the inhibition of HSP70 isoforms

NASA Astrophysics Data System (ADS)

Jones, Alan M.; Westwood, Isaac M.; Osborne, James D.; Matthews, Thomas P.; Cheeseman, Matthew D.; Rowlands, Martin G.; Jeganathan, Fiona; Burke, Rosemary; Lee, Diane; Kadi, Nadia; Liu, Manjuan; Richards, Meirion; McAndrew, Craig; Yahya, Norhakim; Dobson, Sarah E.; Jones, Keith; Workman, Paul; Collins, Ian; van Montfort, Rob L. M.

2016-10-01

The heat shock protein 70s (HSP70s) are molecular chaperones implicated in many cancers and of significant interest as targets for novel cancer therapies. Several HSP70 inhibitors have been reported, but because the majority have poor physicochemical properties and for many the exact mode of action is poorly understood, more detailed mechanistic and structural insight into ligand-binding to HSP70s is urgently needed. Here we describe the first comprehensive fragment-based inhibitor exploration of an HSP70 enzyme, which yielded an amino-quinazoline fragment that was elaborated to a novel ATP binding site ligand with different physicochemical properties to known adenosine-based HSP70 inhibitors. Crystal structures of amino-quinazoline ligands bound to the different conformational states of the HSP70 nucleotide binding domain highlighted the challenges of a fragment-based approach when applied to this particular flexible enzyme class with an ATP-binding site that changes shape and size during its catalytic cycle. In these studies we showed that Ser275 is a key residue in the selective binding of ATP. Additionally, the structural data revealed a potential functional role for the ATP ribose moiety in priming the protein for the formation of the ATP-bound pre-hydrolysis complex by influencing the conformation of one of the phosphate binding loops.

6,7-Dimorpholinoalkoxy quinazoline derivatives as potent EGFR inhibitors with enhanced antiproliferative activities against tumor cells.

PubMed

Zhang, Yaling; Chen, Li; Xu, Hongjiang; Li, Xiabing; Zhao, Lijun; Wang, Wei; Li, Baolin; Zhang, Xiquan

2018-03-10

A series of novel 6,7-dimorpholinoalkoxy quinazoline derivatives was designed, synthesized and evaluated as potent EGFR inhibitors. Most of synthesized derivatives exhibited moderate to excellent antiproliferative activities against five human tumor cell lines. Compound 8d displayed the most remarkable inhibitory activities against tumor cells expressing wild type (A431, A549 and SW480 cells) or mutant (HCC827 and NCI-H1975 cells) epidermal growth factor receptor (EGFR) (with IC 50 values in the range of 0.37-4.87 μM), as well as more potent inhibitory effects against recombinant EGFR tyrosine kinase (EGFR-TK, wt or T790M) (with the IC 50 values of 7.0 and 9.3 nM, respectively). Molecular docking showed that 8d can form four hydrogen bonds with EGFR, and two of them were located in the Asp855-Phe856-Gly857 (DFG) motif of EGFR. Meanwhile, 8d can significantly block EGF-induced EGFR activation and the phosphorylation of its downstream proteins such as Akt and Erk1/2 in human NSCLC cells. Also, 8d mediated cell apoptosis and the prolongation of cell cycle progression in G0/G1-phase in A549 cells. The work would have remarkable implications for further design and development of more potent EGFR tyrosine kinase inhibitors (TKIs). Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Theoretical and vibrational study of N-(3-chloro-4-fluoro-phenyl)-7-methoxy-6-(3-morpholin-4-ylpropoxy)-quinazolin-4-amine (gefitinib)

NASA Astrophysics Data System (ADS)

Mıhçıokur, Özlem; Özpozan, Talat

2015-12-01

N-(3-chloro-4fluoro-phenyl)-7-methoxy-6-(3-morpholin-4ylpropoxy)-quinazolin-4-amine (GEF), a quinalizoline derivative used as new anti-cancer agent, designed to target activity of epidermal growth factor receptor (EGFR) promoting the growth, division and spread of cancer cells, was examined from the vibrational and theoretical point of view. All calculations have been carried out both in gaseous and aqueous phases. In the calculations of both phases, the molecule has been optimized through conformer analysis beginning with the x-ray data. The conformer analyses have been carried out in each phases and the geometrical differences between the most stable structures in gaseous and in aqueous phases have been discussed. The solvent effect for GEF in aqueous solution was simulated by using self-consistent reaction field (SCRF) calculations employing the integral equation formalism variant (IEFPCM) model. NBO analysis has been performed to indicate the presence of intramolecular charge transfer. The complete assignments of the vibrational spectra (IR&Raman) were made with the aid of calculated spectra both in gaseous and aqueous phases. The observed spectral data of the title compound were compared with the calculated spectra obtained by DFT/B3LYP and DFT/B3PW91 methods using 6-31G(d,p) basis set. The theoretical results were found to be in good agreement with the measured experimental data especially for the interpretation of intra molecular interactions.

A dual CCR2/CCR5 chemokine antagonist, BMS-813160? Evaluation of WO2011046916.

PubMed

Norman, Peter

2011-12-01

This application claims the dual CCR2/CCR5 antagonist (S)-1-[(1S,2R,4R)-4-isopropyl(methyl)amino)-2-propylcyclohexyl]-3-(6-(trifluoromethyl)quinazolin-4-ylamino)pyrrolidin-2-one, crystalline form N-1, a process for its preparation and therapeutic uses of it. The compound is shown to be a potent, well-absorbed, drug with a good duration of action. It shows better properties than similar compounds previously claimed by Bristol-Myers Squibb and appears to be a clinical development candidate.

Antimalarial Activities in New Pyrrolo(3,2-f)Quinazoline-1,3-Diamine Derivatives

DTIC Science & Technology

2005-12-01

aminoquinoline drugs (2, 3), water, a highly undesirable physical property for large-scale syn- namely, primaquine and tafenoquine . Central nervous...compounds were determined by a modified Thompson test (1). This test either primaquine or tafenoquine . measures the survivability of mice and parasite...0.625 5/5 3 0.3125 4/5 3 / 0.15625 4/5 3a 0.5 0/2 Tafenoquine 10 5/5 1 2/2 2/2 3 2/2 2.5 4/5 Cured monkeys stayed parasite free for 100 days PT. 1.25

Acid-Base Interactions of Polystyrene Sulfonic Acid in Amorphous Solid Dispersions Using a Combined UV/FTIR/XPS/ssNMR Study.

PubMed

Song, Yang; Zemlyanov, Dmitry; Chen, Xin; Nie, Haichen; Su, Ziyang; Fang, Ke; Yang, Xinghao; Smith, Daniel; Byrn, Stephen; Lubach, Joseph W

2016-02-01

This study investigates the potential drug-excipient interactions of polystyrene sulfonic acid (PSSA) and two weakly basic anticancer drugs, lapatinib (LB) and gefitinib (GB), in amorphous solid dispersions. Based on the strong acidity of the sulfonic acid functional group, PSSA was hypothesized to exhibit specific intermolecular acid-base interactions with both model basic drugs. Ultraviolet (UV) spectroscopy identified red shifts, which correlated well with the color change observed in lapatinib-PSSA solutions. Fourier transform infrared (FTIR) spectra suggest the protonation of the quinazoline nitrogen atom in both model compounds, which agrees well with data from the crystalline ditosylate salt of lapatinib. X-ray photoelectron spectroscopy (XPS) detected increases in binding energy of the basic nitrogen atoms in both lapatinib and gefitinib, strongly indicating protonation of these nitrogen atoms. (15)N solid-state NMR spectroscopy provided direct spectroscopic evidence for protonation of the quinazoline nitrogen atoms in both LB and GB, as well as the secondary amine nitrogen atom in LB and the tertiary amine nitrogen atom in GB. The observed chemical shifts in the LB-PSSA (15)N spectrum also agree very well with the lapatinib ditosylate salt where proton transfer is known. Additionally, the dissolution and physical stability behaviors of both amorphous solid dispersions were examined. PSSA was found to significantly improve the dissolution of LB and GB and effectively inhibit the crystallization of LB and GB under accelerated storage conditions due to the beneficial strong intermolecular acid-base interaction between the sulfonic acid groups and basic nitrogen centers.

Biophysical and X-ray crystallographic analysis of Mps1 kinase inhibitor complexes.

PubMed

Chu, Matthew L H; Lang, Zhaolei; Chavas, Leonard M G; Neres, João; Fedorova, Olga S; Tabernero, Lydia; Cherry, Mike; Williams, David H; Douglas, Kenneth T; Eyers, Patrick A

2010-03-02

The dual-specificity protein kinase monopolar spindle 1 (Mps1) is a central component of the mitotic spindle assembly checkpoint (SAC), a sensing mechanism that prevents anaphase until all chromosomes are bioriented on the metaphase plate. Partial depletion of Mps1 protein levels sensitizes transformed, but not untransformed, human cells to therapeutic doses of the anticancer agent Taxol, making it an attractive novel therapeutic cancer target. We have previously determined the X-ray structure of the catalytic domain of human Mps1 in complex with the anthrapyrazolone kinase inhibitor SP600125. In order to validate distinct inhibitors that target this enzyme and improve our understanding of nucleotide binding site architecture, we now report a biophysical and structural evaluation of the Mps1 catalytic domain in the presence of ATP and the aspecific model kinase inhibitor staurosporine. Collective in silico, enzymatic, and fluorescent screens also identified several new lead quinazoline Mps1 inhibitors, including a low-affinity compound termed Compound 4 (Cpd 4), whose interaction with the Mps1 kinase domain was further characterized by X-ray crystallography. A novel biophysical analysis demonstrated that the intrinsic fluorescence of SP600125 changed markedly upon Mps1 binding, allowing spectrophotometric displacement analysis and determination of dissociation constants for ATP-competitive Mps1 inhibitors. By illuminating the structure of the Mps1 ATP-binding site our results provide novel biophysical insights into Mps1-ligand interactions that will be useful for the development of specific Mps1 inhibitors, including those employing a therapeutically validated quinazoline template.

Synthesis and anticancer activities of 4-(4-substituted piperazin)-5,6,7-trialkoxy quinazoline derivatives.

PubMed

Zhang, Ying; Huang, Yin-Jiu; Xiang, Hong-Mei; Wang, Pei-Yi; Hu, De-Yu; Xue, Wei; Song, Bao-An; Yang, Song

2014-05-06

A series of 4-(4-substituted piperazin)-5,6,7-trialkoxy quinazoline was prepared by conventional heating methods. Among these compounds, the crystal structure of compound 10o (CCDC: 916922) was determined by X-ray crystallography. Bioassay results showed that most target compounds had certain inhibition activities against proliferation of tumor cells, and some compounds even had good broad-spectrum inhibition activities. The ethoxyl series of compounds possessed higher inhibition activities against tumor cells than the methoxyl series of compounds. Bioactivity tests showed that the IC50 values of compound 10s against PC3, MGC803, A375, and A549 cells were 1.8, 2.8, 1.3, and 2.9 μΜ, respectively, which were much higher than those of commercial gefitinib (7.2, 7.6, 7.2, and 9.8 μM, respectively). Conversely, the IC50 values of compound 10s were very low against NH3T3, indicating only weak effect on normal cells as also proven by lactate dehydrogenase and acridine orange/ethidium bromide staining. Analyses of cell configuration and cell cycle revealed that compound 10s possibly caused cells to remain at G0/G1 phase by inhibiting cell proliferation for 24 h. Compound 10s also inhibited the phosphorylation of ERK1/2 and P38 with obvious concentration dependence. Thus, these compounds can inhibit the proliferation of A549 cells through the interruption of ERK1/2 and P38signaling pathways. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

A new flavonol glucoside from the aerial parts of Sida glutinosa.

PubMed

Das, Niranjan; Achari, Basudev; Harigaya, Yoshihiro; Dinda, Biswanath

2011-10-01

Phytochemical investigation on the dried aerial parts of Sida glutinosa has led to the isolation of a new flavonol glucoside, glutinoside (1), along with seven known compounds, 24(28)-dehydromakisterone A (2), 1,2,3,9-tetrahydropyrrolo[2,1-b]-quinazolin-3-amine (3), docosanoic acid, 1-triacontanol, campesterol, stigmasterol, and β-sitosterol. The structures of these compounds were elucidated by means of extensive spectroscopic techniques as well as GC/MS analysis (for sterols) and comparison with the literature data. All these seven known compounds are reported from this plant for the first time.

Cyanuric Acid-Based Organocatalyst for Utilization of Carbon Dioxide at Atmospheric Pressure.

PubMed

Yu, Bing; Kim, Daeun; Kim, Seoksun; Hong, Soon Hyeok

2017-03-22

A organocatalytic system based on economical and readily available cyanuric acid has been developed for the synthesis of 2-oxazolidinones and quinazoline-2,4(1H,3H)-diones from propargylamines and 2-aminobenzonitriles under atmospheric pressure carbon dioxide. Notably, a low concentration of carbon dioxide in air was directly converted into 2-oxazolidinone in excellent yields without an external base. Through mechanistic investigation by in situ FTIR spectroscopy, cyanuric acid was demonstrated to be an efficient catalyst for carbon dioxide fixation. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

One-pot, multicomponent synthesis of 2,3-disubstituted quinazolin-ones with potent and selective activity against Toxoplasma gondii.

PubMed

Brown, Carla E; Kong, Tiffany; Bordón, Claudia; Yolken, Robert; Jones-Brando, Lorraine; McNulty, James

2018-05-15

The discovery of two quinazolinones with selective, single-digit micromolar activity (IC 50  = 6-7 µM) against the tachyzoites of the apicomplexan parasite Toxoplasma gondii is reported. These potent and selective third generation derivatives contain a benzyloxybenzyl substituent at C2 and a bulky aliphatic moiety at N3. Here we show that these quinazolinones inhibit T. gondii tachyzoite replication in an established infection, but do not significantly affect host cell invasion by the tachyzoites. Copyright © 2018 Elsevier Ltd. All rights reserved.

Prazosin induced lysosomal tubulation interferes with cytokinesis and the endocytic sorting of the tumour antigen CD98hc.

PubMed

Fuchs, Robert; Stracke, Anika; Holzmann, Viktoria; Luschin-Ebengreuth, Gerfried; Meier-Allard, Nathalie; Ebner, Nadine; Lassacher, Teresa Maria; Absenger-Novak, Markus; Fröhlich, Eleonore; Schittmayer, Matthias; Cano Crespo, Sara; Palacin, Manuel; Rinner, Beate; Birner-Gruenberger, Ruth

2018-06-15

The quinazoline based drug prazosin (PRZ) is a potent inducer of apoptosis in human cancer cells. We recently reported that PRZ enters cells via endocytosis and induces tubulation of the endolysosomal system. In a proteomics approach aimed at identifying potential membrane proteins with binding affinity to quinazolines, we detected the oncoprotein CD98hc. We confirmed shuttling of CD98hc towards lysosomes and upregulation of CD98hc expression in PRZ treated cells. Gene knockout (KO) experiments revealed that endocytosis of PRZ still occurs in the absence of CD98hc - suggesting that PRZ does not enter the cell via CD98hc but misroutes the protein towards tubular lysosomes. Lysosomal tubulation interfered with completion of cytokinesis and provoked endoreplication. CD98hc KO cells showed reduced endoreplication capacity and lower sensitivity towards PRZ induced apoptosis than wild type cells. Thus, loss of CD98hc does not affect endocytosis of PRZ and lysosomal tubulation, but the ability for endoreplication and survival of cells. Furthermore, we found that glutamine, lysomototropic agents - namely chloroquine and NH 4 Cl - as well as inhibition of v-ATPase, interfere with the intracellular transport of CD98hc. In summary, our study further emphasizes lysosomes as target organelles to inhibit proliferation and to induce cell death in cancer. Most importantly, we demonstrate for the first time that the intracellular trafficking of CD98hc can be modulated by small molecules. Since CD98hc is considered as a potential drug target in several types of human malignancies, our study possesses translational significance suggesting, that old drugs are able to act on a novel target. Copyright © 2018 Elsevier B.V. All rights reserved.

Structural Exploration of Quinazolin-4(3H)-ones as Anticonvulsants: Rational Design, Synthesis, Pharmacological Evaluation, and Molecular Docking Studies.

PubMed

Ugale, Vinod G; Bari, Sanjay B

2016-11-01

Anticonvulsants effective against multiple seizures are of wide interest as antiepileptic drugs, especially if active against pharmaco-resistant seizures. Herein, we synthesized 16 different, rationally designed 2-((6,7-dimethoxy-4-oxo-2-phenylquinazolin-3(4H)-yl)amino)-N-(substituted phenyl)acetamides and screened for anticonvulsant activities through in vivo experiments. Compound 4d emerged as prototype with excellent anti-seizure action in mice against electroshock, chemically induced and pharmaco-resistant 6-Hz seizure models with no symptoms of neurotoxicity and hepatotoxicity (ED 50  = 23.5 mg/kg, MES, mice, i.p.; ED 50  = 32.6 mg/kg, scPTZ, mice, i.p.; ED 50  = 45.2 mg/kg, 6-Hz, mice, i.p.; TD 50  = 325.9 mg/kg, mice, i.p.). In addition, investigation of compound 4l in mice for its pharmacological profile proved it as safer anticonvulsant, devoid of the side effects such as motor dysfunction and hepatotoxicity of classical antiepileptic drugs (ED 50  = 26.1 mg/kg, MES, mice, i.p.; ED 50  = 79.4 mg/kg, scPTZ, mice, i.p.; TD 50  = 361.2 mg/kg, mice, i.p.). We also predicted physiochemical and pharmacokinetic properties of structurally optimized quinazolin-4(3H)-ones by a computational protocol. A combination of in vivo anticonvulsant profile, ex vivo toxicity, and in silico studies suggested that the synthesized compounds may be useful as broad-spectrum anti-seizure drug candidates with favorable pharmacokinetic parameters. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Discovery of a 2,4-Diamino-7-aminoalkoxy-quinazoline as a Potent and Selective Inhibitor of Histone Lysine Methyltransferase G9a†

PubMed Central

Liu, Feng; Chen, Xin; Allali-Hassani, Abdellah; Quinn, Amy M.; Wasney, Gregory A.; Dong, Aiping; Barsyte, Dalia; Kozieradzki, Ivona; Senisterra, Guillermo; Chau, Irene; Siarheyeva, Alena; Kireev, Dmitri B.; Jadhav, Ajit; Herold, J. Martin; Frye, Stephen V.; Arrowsmith, Cheryl H.; Brown, Peter J.; Simeonov, Anton; Vedadi, Masoud; Jin, Jian

2010-01-01

SAR exploration of the 2,4-diamino-6,7-dimethoxyquinazoline template led to the discovery of 8 (UNC0224) as a potent and selective G9a inhibitor. A high resolution X-ray crystal structure of the G9a-8 complex, the first co-crystal structure of G9a with a small molecule inhibitor, was obtained. The co-crystal structure validated our binding hypothesis and will enable structure-based design of novel inhibitors. 8 is a useful tool for investigating the biology of G9a and its roles in chromatin remodeling. PMID:19891491

Optimization of gefitinib analogues with potent anticancer activity.

PubMed

Yin, Kai-Hao; Hsieh, Yi-Han; Sulake, Rohidas S; Wang, Su-Pei; Chao, Jui-I; Chen, Chinpiao

2014-11-15

The interactions of gefitinib (Iressa) in EGFR are hydrogen bonding and van der Waals forces through quinazoline and aniline rings. However the morpholino group of gefitinib is poorly ordered due to its weak electron density. A series of novel piperazino analogues of gefitinib where morpholino group substituted with various piperazino groups were designed and synthesized. Most of them indicated significant anti-cancer activities against human cancer cell lines. In particular, compounds 52-54 showed excellent potency against cancer cells. Convergent synthetic approach has been developed for the synthesis of gefitinib intermediate which can lead to gefitinib as well as numerous analogues. Copyright © 2014 Elsevier Ltd. All rights reserved.

Synthesis and antitumour activity of 4-aminoquinazoline derivatives

NASA Astrophysics Data System (ADS)

Lipunova, G. N.; Nosova, E. V.; Charushin, V. N.; Chupakhin, O. N.

2016-07-01

Pieces of data on the synthesis and antitumour activity of 4-aminoquinazolines are summarized and analyzed. Key methods for the synthesis of these compounds are considered, primarily cyclocondensation of carboxylic acid derivatives, as well as the oxidation of quinazolines and the cyclization of disubstituted thioureas. Improvements of synthetic schemes for erlotinib, gefitinib and lapatinib, which are the best-known pharmaceuticals based on compounds of the title class, are also considered. Synthetic strategies and biological activities for new 4-aminoquinazoline derivatives that are EGFR-tyrosine kinase inhibitors, multiactive compounds, and labelled compounds for use as positron emission tomography (PET) imaging agents are discussed. The bibliography includes 263 references.

Identification and Development of 2,3-Dihydropyrrolo[1,2-a]quinazolin-5(1H)-one Inhibitors Targeting Bromodomains within the Switch/Sucrose Nonfermenting Complex

PubMed Central

2016-01-01

Bromodomain containing proteins PB1, SMARCA4, and SMARCA2 are important components of SWI/SNF chromatin remodeling complexes. We identified bromodomain inhibitors that target these proteins and display unusual binding modes involving water displacement from the KAc binding site. The best compound binds the fifth bromodomain of PB1 with a KD of 124 nM, SMARCA2B and SMARCA4 with KD values of 262 and 417 nM, respectively, and displays excellent selectivity over bromodomains other than PB1, SMARCA2, and SMARCA4. PMID:27119626

Highly efficient induction of chirality in intramolecular

PubMed

Cossio; Arrieta; Lecea; Alajarin; Vidal; Tovar

2000-06-16

Highly stereocontrolled, intramolecular [2 + 2] cycloadditions between ketenimines and imines leading to 1,2-dihydroazeto[2, 1-b]quinazolines have been achieved. The source of stereocontrol is a chiral carbon atom adjacent either to the iminic carbon or nitrogen atom. In the first case, the stereocontrol stems from the preference for the axial conformer in the first transition structure. In the second case, the origin of the stereocontrol lies on the two-electron stabilizing interaction between the C-C bond being formed and the sigma orbital corresponding to the polar C-X bond, X being an electronegative atom. These models can be extended to other related systems for predicting the stereochemical outcome in this intramolecular reaction.

Synthesis of febrifugine derivatives and development of an effective and safe tetrahydroquinazoline-type antimalarial.

PubMed

Kikuchi, Haruhisa; Horoiwa, Seiko; Kasahara, Ryota; Hariguchi, Norimitsu; Matsumoto, Makoto; Oshima, Yoshiteru

2014-04-09

Febrifugine, a quinazoline alkaloid isolated from Dichroa febrifuga roots, shows powerful antimalarial activity against Plasmodium falciparum. Although the use of ferifugine as an antimalarial drug has been precluded because of its severe side effects, its potent antimalarial activity has stimulated medicinal chemists to pursue its derivatives instead, which may provide valuable leads for novel antimalarial drugs. In the present study, we synthesized new derivatives of febrifugine and evaluated their in vitro and in vivo antimalarial activities to develop antimalarials that are more effective and safer. As a result, we proposed tetrahydroquinazoline-type derivative as a safe and effective antimalarial candidate. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

A comparative meta-genomic analysis of HPV strains: A step towards the design, synthesis and characterization of noval quenazoline derivative for antiviral activity.

PubMed

Dhanaraj, Premnath; Devadas, Akila; Muthiah, Indiraleka

2018-04-01

Epigenetic characterization studies have clearly shown that the association of genital Human Papilloma Virus (HPV) with cervical cancer is strong, independent of other risk factors, and consistent in several countries. Even though all the strains of Human Papilloma Virus can cause cancer, the high-risk strains can cause severe cancer in a human. The E6 and E7 protein are responsible for the carcinogenic property of HPV. Among these two proteins, the HPV E7 protein plays a major role in the viral life cycle by allowing the virus to replicate in differentiating epithelial cells. All the strains of HPV are variants (High risk and low risk). A computational analysis study is done to find which low-risk strain is showing most similarity with the high risk there by predicting that this low-risk strain can be converted to high-risk if a mutation occurs in future. Through mutation, a normal strain will get converted to low-risk and a low-risk to high-risk. So the mutations are important and it can affect the viruses to a greater extent because of their smaller size. In order to inhibit the expression of Type 11 low-risk strain a noval suppressor molecule is synthesized and characterized using UV, FTIR and NMR spectrometry. The suppressor molecule is a quinazoline derivative, as it can act as an anti-cancer agent to inhibit the expression of the E7 protein in Type 11 strain. The efficiency of binding of type 11 E7 protein with quinazoline derivative is calculated through docking studies using G-Score (Schrodinger). Thus proposing this noval suppressor molecule can be lead against cervical cancer caused by HPV Type 11 strain after further in-vitro and in vivo characterization. Copyright © 2018 Elsevier Ltd. All rights reserved.

Stability Characterization of Quinazoline Derivative BG1188 by Optical Methods

NASA Astrophysics Data System (ADS)

Militaru, Andra; Smarandache, Adriana; Mahamoud, Abdallah; Damian, Victor; Ganea, Paul; Alibert, Sandrine; Pagès, Jean-Marie; Pascu, Mihail-Lucian

2011-08-01

3-[2-(dimethylamino)ethyl]-6-nitroquinazolin-4(3H)-one, labeled BG1188, is a new synthesized compound, out of a series of quinazoline derivatives developed to fight the multidrug resistance of antibiotics acquired by bacteria. A characterization of the BG1188 powder was made using FTIR spectra in order to evidence the functional groups in the medicine's molecule. The ultraviolet-visible (UV-Vis) absorption spectra were used to study the stability of the BG1188 solutions in two solvents and at different temperatures. BG1188 concentration in ultrapure water was varied between 2×10-3 M (stock solution) and 10-6 M. The concentration recommended by higher activity on bacteria was 10-3 M. For the same reason, this was the utilized concentration of BG1188 in dimethyl sulfoxide (DMSO). Time stability was characterized by comparing the time evolution of the UV-Vis absorption spectra of the BG1188 solutions in ultrapure de-ionized water or in DMSO. The spectra were recorded daily for about 4 months after the preparation for the BG1188 solutions in ultrapure water. Generally, samples are stable within the experimental errors at concentrations higher than 10-5 M, but the stability time interval may vary from 119 days at 10-4 M to 34 days at 10-5 M. Time evolution of the absorption spectra at 10-3 M in ultrapure water shows reproducibility within the measuring errors (±1.045%) for time intervals up to 1032 hours (more than 40 days) after preparation. On the other hand, BG1188 solutions in DMSO may be considered unstable because the absorption spectra modify in terms of peak shapes and intensities, indicating that the samples exhibit modifications immediately after preparation. Regardless the solvent used, some aggregation phenomena took place and wire-like aggregates were observed in all the solutions with the naked eye. These aggregates were analyzed, tentatively, using optical microscopy and FTIR.

Pharmacokinetics, safety, and efficacy of a liposome encapsulated thymidylate synthase inhibitor, OSI-7904L [(S)-2-[5-[(1,2-dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)methyl]amino-1-oxo-2-isoindolynl]-glutaric acid] in mice.

PubMed

Desjardins, John; Emerson, David L; Colagiovanni, Dorothy B; Abbott, Elizabeth; Brown, Eric N; Drolet, Daniel W

2004-06-01

OSI-7904L [(S)-2-[5-[(1,2-dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)methyl]amino-1-oxo-2-isoindolynl]-glutaric acid] is a liposomal formulation of the highly specific, noncompetitive, thymidylate synthase inhibitor OSI-7904 (also known as GW1843, 1843U89, and GS7904). The liposome formulation was developed to enhance the therapeutic index and dose schedule convenience of this potent antifolate compound. The studies presented here were conducted to determine the antitumor efficacy, distribution, pharmacokinetics, and safety of OSI-7904L in mice. In a human colon adenocarcinoma xenograft model in mice, OSI-7904L demonstrated superior antitumor efficacy compared with OSI-7904 or 5-fluorouracil. Furthermore, OSI-7904L could be administered less frequently than OSI-7904 although still generating greater tumor growth inhibition. Distribution studies confirmed that OSI-7904L-treated animals had much greater plasma, tissue, and tumor exposure than did OSI-7904-treated animals. Tumor exposures, based on area under the curve, in OSI-7904L-treated mice were increased over 100-fold compared with tumor exposures in OSI-7904-treated mice. Plasma exposures following OSI-7904L administration were greater than dose proportional consistent with saturation of plasma clearance mechanisms. OSI-7904L was much more toxic than OSI-7904 in the mouse with primary toxicities to the intestines, bone marrow, and thymus. Minimal toxicity to the lungs and liver was noted. These data clearly demonstrated that in mice, OSI-7904L has an increased plasma residence time as well as increased tissue and tumor exposure compared with OSI-7904, thus resulting in increased potency and toxicity. Potential benefits of OSI-7904L include improved efficacy and a more convenient schedule of administration.

Development of α-glucosidase inhibitors by room temperature C-C cross couplings of quinazolinones.

PubMed

Garlapati, Ramesh; Pottabathini, Narender; Gurram, Venkateshwarlu; Kasani, Kumara Swamy; Gundla, Rambabu; Thulluri, Chiranjeevi; Machiraju, Pavan Kumar; Chaudhary, Avinash B; Addepally, Uma; Dayam, Raveendra; Chunduri, Venkata Rao; Patro, Balaram

2013-08-07

Novel quinazolinone based α-glucosidase inhibitors have been developed. For this purpose a virtual screening model has been generated and validated utilizing acarbose as a α-glucosidase inhibitor. Homology modeling, docking, and virtual screening were successfully employed to discover a set of structurally diverse compounds active against α-glucosidase. A search of a 3D database containing 22,500 small molecules using the structure based virtual model yielded ten possible candidates. All ten candidates were N-3-pyridyl-2-cyclopropyl quinazolinone-4-one derivatives, varying at the 6 position. This position was modified by Suzuki-Miyaura cross coupling with aryl, heteroaryl, and alkyl boronic acids. A catalyst screen was performed, and using the best optimal conditions, a series of twenty five compounds was synthesized. Notably, the C-C cross coupling reactions of the 6-bromo-2-cyclopropyl-3-(pyridyl-3-ylmethyl)quinazolin-4(3H)-one precursor have been accomplished at room temperature. A comparison of the relative reactivities of 6-bromo and 6-chloro-2,3-disubstituted quinazolinones with phenyl boronic acid was conducted. An investigation of pre-catalyst loading for the reaction of the 6-bromo-2-cyclopropyl-3-(pyridyl-3-ylmethyl)quinazolin-4(3H)-one substrate was also carried out. Finally, we submitted our compounds to biological assays against α-glucosidase inhibitors. Of these, three hits (compounds 4a, 4t and 4r) were potentially active as α-glucosidase inhibitors and showed activity with IC50 values <20 μM. Based on structural novelty and desirable drug-like properties, 4a was selected for structure-activity relationship study, and thirteen analogs were synthesized. Nine out of thirteen analogs acted as α-glucosidase inhibitors with IC50 values <10 μM. These lead compounds have desirable physicochemical properties and are excellent candidates for further optimization.

A chemical corrector modifies the channel function of F508del-CFTR.

PubMed

Kim Chiaw, Patrick; Wellhauser, Leigh; Huan, Ling Jun; Ramjeesingh, Mohabir; Bear, Christine E

2010-09-01

The deletion of Phe-508 (F508del) constitutes the most prevalent cystic fibrosis-causing mutation. This mutation leads to cystic fibrosis transmembrane conductance regulator (CFTR) misfolding and retention in the endoplasmic reticulum and altered channel activity in mammalian cells. This folding defect can however be partially overcome by growing cells expressing this mutant protein at low (27 degrees C) temperature. Chemical "correctors" have been identified that are also effective in rescuing the biosynthetic defect in F508del-CFTR, thereby permitting its functional expression at the cell surface. The mechanism of action of chemical correctors remains unclear, but it has been suggested that certain correctors [including 4-cyclohexyloxy-2-(1-[4-(4-methoxy-benzenesulfonyl)-piperazin-1-yl]-ethyl)-quinazoline (VRT-325)] may act to promote trafficking by interacting directly with the mutant protein. To test this hypothesis, we assessed the effect of VRT-325 addition on the channel activity of F508del-CFTR after its surface expression had been "rescued" by low temperature. It is noteworthy that short-term pretreatment with VRT-325 [but not with an inactive analog, 4-hydroxy-2-(1-[4-(4-methoxy-benzenesulfonyl)-piperazin-1-yl]-ethyl)-quinazoline (VRT-186)], caused a modest but significant inhibition of cAMP-mediated halide flux. Furthermore, VRT-325 decreased the apparent ATP affinity of purified and reconstituted F508del-CFTR in our ATPase activity assay, an effect that may account for the decrease in channel activity by temperature-rescued F508del-CFTR. These findings suggest that biosynthetic rescue mediated by VRT-325 may be conferred (at least in part) by direct modification of the structure of the mutant protein, leading to a decrease in its ATP-dependent conformational dynamics. Therefore, the challenge for therapy discovery will be the design of small molecules that bind to promote biosynthetic maturation of the major mutant without compromising its activity in vivo.

Investigation on Quantitative Structure Activity Relationships of a Series of Inducible Nitric Oxide.

PubMed

Sharma, Mukesh C; Sharma, S

2016-12-01

A series of 2-dihydro-4-quinazolin with potent highly selective inhibitors of inducible nitric oxide synthase activities was subjected to quantitative structure activity relationships (QSAR) analysis. Statistically significant equations with high correlation coefficient (r 2  = 0.8219) were developed. The k-nearest neighbor model has showed good cross-validated correlation coefficient and external validation values of 0.7866 and 0.7133, respectively. The selected electrostatic field descriptors the presence of blue ball around R1 and R4 in the quinazolinamine moiety showed electronegative groups favorable for nitric oxide synthase activity. The QSAR models may lead to the structural requirements of inducible nitric oxide compounds and help in the design of new compounds.

Diastereoselective reactions in glycine templates containing an ent-ardeemin fragment.

PubMed

Martín-Santamaría, Sonsoles; Corzo-Suárez, Raúl; Avendaño, Carmen; Espada, Modesta; Gago, Federico; García-Granda, Santiago; Rzepa, Henry S

2002-04-05

Self-consistent reaction field solvation models derived from SCF-MO calculations are shown to be reliable in modeling the diastereoselectivity of the reactions of the anion and cation derived from (4S)-2,4-dimethyl-2,4-dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-dione (1) at C(1) with electrophiles and nucleophiles, respectively. The found anti/syn ratio of compound 8, which is a seco-ent-ardeemin analogue obtained by alkylation of 1 with gramine methiodide, confirms this computational model. A close similarity between the calculated geometry of the piperazine ring in the anti isomers of 1,2,4-trialkyl derivatives and that deduced from their (1)H NMR (solution) and X-ray data has been also established.

Anthranilate-Activating Modules from Fungal Nonribosomal Peptide Assembly Lines†

PubMed Central

Ames, Brian D.; Walsh, Christopher T.

2010-01-01

Fungal natural products containing benzodiazepinone- and quinazolinone-fused ring systems can be assembled by nonribosomal peptide synthetases (NRPS) using the conformationally restricted β-amino acid anthranilate as one of the key building blocks. We validated that the first module of the acetylaszonalenin synthetase of Neosartorya fischeri NRRL 181 activates anthranilate to anthranilyl-AMP. With this as starting point, we then used bioinformatic predictions about fungal adenylation domain selectivities to identify and confirm an anthranilate-activating module in the fumiquinazoline A producer Aspergillus fumigatus Af293 as well as a second anthranilate-activating NRPS in N. fischeri. This establishes an anthranilate adenylation domain code for fungal NRPS and should facilitate detection and cloning of gene clusters for benzodiazepine- and quinazoline-containing polycyclic alkaloids with a wide range of biological activities. PMID:20225828

Novel quinazoline-based sulfonamide derivative (3D) induces apoptosis in colorectal cancer by inhibiting JAK2-STAT3 pathway.

PubMed

Al-Obeed, Omar; Vaali-Mohammed, Mansoor-Ali; Eldehna, Wagdy M; Al-Khayal, Khayal; Mahmood, Amer; Abdel-Aziz, Hatem A; Zubaidi, Ahmed; Alafeefy, Ahmed; Abdulla, Maha; Ahmad, Rehan

2018-01-01

Colorectal cancer (CRC) is a major worldwide health problem owing to its high prevalence and mortality rate. Developments in screening, prevention, biomarker, personalized therapies and chemotherapy have improved detection and treatment. However, despite these advances, many patients with advanced metastatic tumors still succumb to the disease. New anticancer agents are needed for treating advanced stage CRC as most of the deaths occur due to cancer metastasis. A recently developed novel sulfonamide derivative 4-((2-(4-(dimethylamino) phenyl)quinazolin-4-yl)amino)benzenesulfonamide (3D) has shown potent antitumor effect; however, the mechanism underlying the antitumor effect remains unknown. 3D-mediated inhibition on cell viability was evaluated by MTT and real-time cell proliferation was measured by xCelligence RTDP instrument. Western blotting was used to measure pro-apoptotic, anti-apoptotic proteins and JAK2-STAT3 phosphorylation. Flow cytometry was used to measure ROS production and apoptosis. Our study revealed that 3D treatment significantly reduced the viability of human CRC cells HT-29 and SW620. Furthermore, 3D treatment induced the generation of reactive oxygen species (ROS) in human CRC cells. Confirming our observation, N-acetylcysteine significantly inhibited apoptosis. This is further evidenced by the induction of p53 and Bax; release of cytochrome c; activation of caspase-9, caspase-7 and caspase-3; and cleavage of PARP in 3D-treated cells. This compound was found to have a significant effect on the inhibition of antiapoptotic proteins Bcl2 and BclxL. The results further demonstrate that 3D inhibits JAK2-STAT3 pathway by decreasing the constitutive and IL-6-induced phosphorylation of STAT3. 3D also decreases STAT3 target genes such as cyclin D1 and survivin. Furthermore, a combination study of 3D with doxorubicin (Dox) also showed more potent effects than single treatment of Dox in the inhibition of cell viability. Taken together, these findings indicate that 3D induces ROS-mediated apoptosis and inhibits JAK2-STAT3 signaling in CRC.

Discovery of novel 4-anilinoquinazoline derivatives as potent inhibitors of epidermal growth factor receptor with antitumor activity.

PubMed

Xu, Yun-Yun; Li, Si-Ning; Yu, Gao-Jian; Hu, Qing-Hua; Li, Huan-Qiu

2013-10-01

Two new series of new compounds containing a 6-amino-substituted group or 6-acrylamide-substituted group linked to a 4-anilinoquinazoline nucleus have been discovered as potential EGFR inhibitors. These compounds proved efficient effects on antiproliferative activity and EGFR-TK inhibitory activity. Especially, N(6)-((5-bromothiophen-2-yl)methyl)-N(4)-(3-chlorophenyl)quinazoline-4,6-diamine (5e), showed the most potent inhibitory activity (IC50=3.11μM for Hep G2, IC50=0.82μM for A549). The EGFR molecular docking model suggested that the new compound is nicely bound to the region of EGFR, and cell morphology by Hoechst stain experiment suggested that these compounds efficiently induced apoptosis of A549 cells. Copyright © 2013 Elsevier Ltd. All rights reserved.

Properly Substituted Analogues of BIX-01294 Lose Inhibition of G9a Histone Methyltransferase and Gain Selective Anti-DNA Methyltransferase 3A Activity

PubMed Central

Rotili, Dante; Tarantino, Domenico; Marrocco, Biagina; Gros, Christina; Masson, Véronique; Poughon, Valérie; Ausseil, Fréderic; Chang, Yanqi; Labella, Donatella; Cosconati, Sandro; Di Maro, Salvatore; Novellino, Ettore; Schnekenburger, Michael; Grandjenette, Cindy; Bouvy, Celine; Diederich, Marc; Cheng, Xiaodong; Arimondo, Paola B.; Mai, Antonello

2014-01-01

Chemical manipulations performed on the histone H3 lysine 9 methyltransferases (G9a/GLP) inhibitor BIX-01294 afforded novel desmethoxyquinazolines able to inhibit the DNA methyltransferase DNMT3A at low micromolar levels without any significant inhibition of DNMT1 and G9a. In KG-1 cells such compounds, when tested at sub-toxic doses, induced the luciferase re-expression in a stable construct controlled by a cytomegalovirus (CMV) promoter silenced by methylation (CMV-luc assay). Finally, in human lymphoma U-937 and RAJI cells, the N-(1-benzylpiperidin-4-yl)-2-(4-phenylpiperazin-1-yl)quinazolin-4-amine induced the highest proliferation arrest and cell death induction starting from 10 µM, in agreement with its DNMT3A inhibitory potency. PMID:24810902

Quantitative determination of the dual COX-2/5-LOX inhibitor tryptanthrin in Isatis tinctoria by ESI-LC-MS.

PubMed

Danz, Henning; Baumann, Dietmar; Hamburger, Matthias

2002-02-01

Isatis tinctoria L. is an old European and Chinese dye plant and anti-inflammatory herb from which the potent cyclooxygenase-2 and 5-lipoxygenase inhibitor tryptanthrin (1) (indolo-[2,1-b]-quinazoline-6,12-dione) was recently isolated as one of the active principles. An HPLC method for the quantitative analysis of the compound in plant material was developed. Reproducible extraction was achieved by accelerated solvent extraction (ASE). Detection by UV at 254 and 387 nm and by electrospray-MS were compared. The low tryptanthrin content in the herb and possible interferences required isocratic high-performance liquid chromatography coupled with electrospray-MS in single ion mode. More than 70 Isatis samples of different origin were analyzed. The tryptanthrin content in leaf samples varied from 0.56 to 16.74 x 10(-3) %.

Three-dimensional quantitative structure-activity relationship studies on c-Src inhibitors based on different docking methods.

PubMed

Bairy, Santhosh Kumar; Suneel Kumar, B V S; Bhalla, Joseph Uday Tej; Pramod, A B; Ravikumar, Muttineni

2009-04-01

c-Src kinase play an important role in cell growth and differentiation and its inhibitors can be useful for the treatment of various diseases, including cancer, osteoporosis, and metastatic bone disease. Three dimensional quantitative structure-activity relationship (3D-QSAR) studies were carried out on quinazolin derivatives inhibiting c-Src kinase. Molecular field analysis (MFA) models with four different alignment techniques, namely, GLIDE, GOLD, LIGANDFIT and Least squares based methods were developed. glide based MFA model showed better results (Leave one out cross validation correlation coefficient r(2)(cv) = 0.923 and non-cross validation correlation coefficient r(2)= 0.958) when compared with other models. These results help us to understand the nature of descriptors required for activity of these compounds and thereby provide guidelines to design novel and potent c-Src kinase inhibitors.

KRAS G12C Drug Development: Discrimination between Switch II Pocket Configurations Using Hydrogen/Deuterium-Exchange Mass Spectrometry

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lu, Jia; Harrison, Rane A.; Li, Lianbo

KRAS G12C, the most common RAS mutation found in non-small-cell lung cancer, has been the subject of multiple recent covalent small-molecule inhibitor campaigns including efforts directed at the guanine nucleotide pocket and separate work focused on an inducible pocket adjacent to the switch motifs. Multiple conformations of switch II have been observed, suggesting that switch II pocket (SIIP) binders may be capable of engaging a range of KRAS conformations. Here we report the use of hydrogen/deuterium-exchange mass spectrometry (HDX MS) to discriminate between conformations of switch II induced by two chemical classes of SIIP binders. We investigated the structural basismore » for differences in HDX MS using X-ray crystallography and discovered a new SIIP configuration in response to binding of a quinazoline chemotype. These results have implications for structure-guided drug design targeting the RAS SIIP.« less

Alkaloids as Cyclooxygenase Inhibitors in Anticancer Drug Discovery.

PubMed

Hashmi, Muhammad Ali; Khan, Afsar; Farooq, Umar; Khan, Sehroon

2018-01-01

Cancer is the leading cause of death worldwide and anticancer drug discovery is a very hot area of research at present. There are various factors which control and affect cancer, out of which enzymes like cyclooxygenase-2 (COX-2) play a vital role in the growth of tumor cells. Inhibition of this enzyme is a very useful target for the prevention of various types of cancers. Alkaloids are a diverse group of naturally occurring compounds which have shown great COX-2 inhibitory activity both in vitro and in vivo. In this mini-review, we have discussed different alkaloids with COX-2 inhibitory activities and anticancer potential which may act as leads in modern anticancer drug discovery. Different classes of alkaloids including isoquinoline alkaloids, indole alkaloids, piperidine alkaloids, quinazoline alkaloids, and various miscellaneous alkaloids obtained from natural sources have been discussed in detail in this review. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Novel 4-Thiazolidinone Derivatives as Anti-Infective Agents: Synthesis, Characterization, and Antimicrobial Evaluation.

PubMed

Gupta, Amit; Singh, Rajendra; Sonar, Pankaj K; Saraf, Shailendra K

2016-01-01

A series of new 4-thiazolidinone derivatives was synthesized, characterized by spectral techniques, and screened for antimicrobial activity. All the compounds were evaluated against five Gram-positive bacteria, two Gram-negative bacteria, and two fungi, at concentrations of 50, 100, 200, 400, 800, and 1600 µg/mL, respectively. Minimum inhibitory concentrations of all the compounds were also determined and were found to be in the range of 100-400 µg/mL. All the compounds showed moderate-to-good antimicrobial activity. Compounds 4a [2-(4-fluoro-phenyl)-3-(4-methyl-5,6,7,8-tetrahydro-quinazolin-2-yl)-thiazolidin-4-one] and 4e [3-(4,6-dimethyl-pyrimidin-2-yl)-2-(2-methoxy-phenyl)-thiazolidin-4-one] were the most potent compounds of the series, exhibiting marked antimicrobial activity against Pseudomonas fluorescens, Staphylococcus aureus, and the fungal strains. Thus, on the basis of results obtained, it may be concluded that synthesized compounds exhibit a broad spectrum of antimicrobial activity.

Structure-Based Design, Synthesis, Biological Evaluation, and Molecular Docking of Novel PDE10 Inhibitors with Antioxidant Activities

NASA Astrophysics Data System (ADS)

Li, Jinxuan; Chen, Jing-Yi; Deng, Ya-Lin; Zhou, Qian; Wu, Yinuo; Wu, Deyan; Luo, Hai-Bin

2018-05-01

Phosphodiesterase 10 is a promising target for the treatment of a series of central nervous system (CNS) diseases. Imbalance between oxidative stress and antioxidant defense systems as a universal condition in neurodegenerative disorders is widely studied as a potential therapy for CNS diseases, such as Alzheimer’s disease (AD), Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS). To discover multifunctional pharmaceuticals as a treatment for neurodegenerative diseases, a series of quinazoline-based derivatives with PDE10 inhibitory activities and antioxidant activities were designed and synthesized. Nine out of thirteen designed compounds showed good PDE10 inhibition at the concentration of 1.0 μM. Among these compounds, eight exhibited moderate to excellent antioxidant activity with ORAC (oxygen radical absorbance capacity) value above 1.0. Molecular docking was performed for better understanding of the binding patterns of these compounds with PDE10. Compound 11e, which showed remarkable inhibitory activity against PDE10 and antioxidant activity may serve as a lead for the further modification.

An efficient one-pot two catalyst system in the construction of 2-substituted benzimidazoles: synthesis of benzimidazo[1,2-c]quinazolines.

PubMed

Cimarelli, Cristina; Di Nicola, Matteo; Diomedi, Simone; Giovannini, Riccardo; Hamprecht, Dieter; Properzi, Roberta; Sorana, Federico; Marcantoni, Enrico

2015-12-28

The benzimidazole core is a common moiety in a large number of natural products and pharmacologically active small molecules. The synthesis of novel benzimidazole derivatives remains a main focus in medicinal research. In continuation of the efforts towards Ce(III) catalysts for organic transformations, we observed for the first time the activity of the iodide ion and copper cation in activating CeCl3·7H2O in the selective formation of prototypical 2-substituted benzimidazoles. The one-pot CeCl3·7H2O-CuI catalytic system procedure includes the cyclo-dehydrogenation of aniline Schiff's bases, generated in situ from the condensation of 1,2-phenylenediamine and aldehydes, followed by the oxidation with iodine, which works as a hydrogen sponge. Mild reaction conditions, good to excellent yields, and clean reactions make the procedure a useful contribution to the synthesis of biologically active fused heterocycles containing benzimidazoquinazolines.

Azole-Anion-Based Aprotic Ionic Liquids: Functional Solvents for Atmospheric CO2 Transformation into Various Heterocyclic Compounds.

PubMed

Zhao, Yanfei; Wu, Yunyan; Yuan, Guangfeng; Hao, Leiduan; Gao, Xiang; Yang, Zhenzhen; Yu, Bo; Zhang, Hongye; Liu, Zhimin

2016-10-06

The chemical transformation of atmospheric CO 2 is of great significance yet still poses a great challenge. Herein, azole-anion-based aprotic ionic liquids (ILs) were synthesized by the deprotonation of weak proton donors (e.g., 2-methylimidazole, 4-methylimidazole, and 2,4-dimethylimidazole) with tetrabutylphosphonium hydroxide, [Bu 4 P][OH]. We found that these ILs, such as [Bu 4 P][2-MIm], could activate atmospheric CO 2 through the formation of carbamates. The resultant carbamate intermediates could further react with various types of substrate, including propargylic alcohols, 2-aminobenzonitriles, ortho-phenylenediamines, and 2-aminothiophenol, thereby producing α-alkylidene cyclic carbonates, quinazoline-2,4(1 H,3 H)-diones, benzimidazolones, and benzothiazoline, respectively, in moderate-to-good yields. Thus, we have achieved the transformation of CO 2 at atmospheric pressure, and we expect this method to open up new routes for the synthesis of various oxygen-containing heterocyclic compounds under metal-free conditions. © 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

A comparative study on the skin penetration of pure tryptanthrin and tryptanthrin in Isatis tinctoria extract by dermal microdialysis coupled with isotope dilution ESI-LC-MS.

PubMed

Oberthür, Christine; Heinemann, Christian; Elsner, Peter; Benfeldt, Eva; Hamburger, Matthias

2003-05-01

The indolo[2,1- b]quinazoline alkaloid tryptanthrin has recently been identified as a pharmacologically active compound in Isatis tinctoria, with potent dual inhibitory activity on prostaglandin and leukotriene synthesis. To investigate the skin penetration of tryptanthrin from solutions of pure compound and Isatis extracts, we developed and validated a cutaneous microdialysis model using ex vivo pig foreleg. Microdialysis was performed by placing linear probes in the dermis of the skin in situ, and tryptanthrin concentrations in the dialysates were determined by isotope dilution electrospray ionization LC-MS in the selected ion mode. Measurable concentrations of tryptanthrin were detected 30 min after application. A dose-dependent increase in tryptanthrin concentrations in the dialysate was observed for the Isatis extracts, but not for pure tryptanthrin. Microscopic analysis showed that the pure compound crystallized from the solution but remained in an amorphous state in the extracts.

Novel small molecule induces p53-dependent apoptosis in human colon cancer cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Park, Sang Eun; Min, Yong Ki; Ha, Jae Du

2007-07-06

Using high-throughput screening with small-molecule libraries, we identified a compound, KCG165 [(2-(3-(2-(pyrrolidin-1-yl)ethoxy)-1,10b-dihydro-[1,2,4]triazolo[1,5-c] quinazolin-5(6H)-one)], which strongly activated p53-mediated transcriptional activity. KCG165-induced phosphorylations of p53 at Ser{sup 6}, Ser{sup 15}, and Ser{sup 20}, which are all key residues involved in the activation and stabilization of p53. Consistent with these findings, KCG165 increased level of p53 protein and led to the accumulation of transcriptionally active p53 in the nucleus with the increased occupancy of p53 in the endogenous promoter region of its downstream target gene, p21{sup WAF1/CIP}. Notably, KCG165-induced p53-dependent apoptosis in cancer cells. Furthermore, we suggested topoisomerase II as the molecular targetmore » of KCG165. Together, these results indicate that KCG165 may have potential applications as an antitumor agent.« less

Integrated CO2 capture-fixation chemistry via interfacial ionic liquid catalyst in laminar gas/liquid flow

NASA Astrophysics Data System (ADS)

Vishwakarma, Niraj K.; Singh, Ajay K.; Hwang, Yoon-Ho; Ko, Dong-Hyeon; Kim, Jin-Oh; Babu, A. Giridhar; Kim, Dong-Pyo

2017-03-01

Simultaneous capture of carbon dioxide (CO2) and its utilization with subsequent work-up would significantly enhance the competitiveness of CO2-based sustainable chemistry over petroleum-based chemistry. Here we report an interfacial catalytic reaction platform for an integrated autonomous process of simultaneously capturing/fixing CO2 in gas-liquid laminar flow with subsequently providing a work-up step. The continuous-flow microreactor has built-in silicon nanowires (SiNWs) with immobilized ionic liquid catalysts on tips of cone-shaped nanowire bundles. Because of the superamphiphobic SiNWs, a stable gas-liquid interface maintains between liquid flow of organoamines in upper part and gas flow of CO2 in bottom part of channel. The intimate and direct contact of the binary reagents leads to enhanced mass transfer and facilitating reactions. The autonomous integrated platform produces and isolates 2-oxazolidinones and quinazolines-2,4(1H,3H)-diones with 81-97% yields under mild conditions. The platform would enable direct CO2 utilization to produce high-valued specialty chemicals from flue gases without pre-separation and work-up steps.

Activation of Wnt3α/β-catenin signal pathway attenuates apoptosis of the cerebral microvascular endothelial cells induced by oxygen-glucose deprivation.

PubMed

Zhang, Jianshui; Zhang, Junfeng; Qi, Cunfang; Yang, Pengbo; Chen, Xinlin; Liu, Yong

2017-08-19

Brain microvascular endothelial cells (BMECs) play vital roles in cerebral ischemia, during which many signal pathways mediate BMECs apoptosis. In this study, we explored the potential role of Wnt3α/β-catenin signal in BMECs apoptosis induced by ischemia. Here, we found that oxygen-glucose deprivation (OGD) could induce apoptosis of BMECs with Wnt3a mRNA expression decrease. Meanwhile, activation Wnt3a/β-catenin signal with exogenous Wnt3α protein (100 ng/ml) or Lithium Chloride (LiCl, 4 mM) decreased significantly apoptosis of BMECs induced by OGD with increasing expression of Bcl-2 in the whole cell and β-catenin in the nucleus. But, inhibition Wnt3a/β-catenin signal with DKK1 (100 ng/ml) or 2.4-diamino quinazoline (DQ, 0.2 μM) increased apoptosis of BMECs with decreasing expression of Bcl-2. These results suggest that activation Wnt3α/β-catenin signal attenuate apoptosis of BMECs induced by ischemia. Copyright © 2017 Elsevier Inc. All rights reserved.

Alkaloids as important scaffolds in therapeutic drugs for the treatments of cancer, tuberculosis, and smoking cessation.

PubMed

Kittakoop, Prasat; Mahidol, Chulabhorn; Ruchirawat, Somsak

2014-01-01

Alkaloid molecules can act, depending on a type of amine functionality present in alkalods, as either hydrogenacceptor or hydrogen-donor for hydrogen bonding that is critically important for the interaction (binding) between targets (enzymes, proteins and receptors) and drugs (ligands). Because of this unique property, alkaloid scaffolds are therefore present in several drugs and lead compounds. This review highlights alkaloid scaffolds in drugs, particularly those recently approved in 2012; it also covers the scaffolds in leads and drug candidates which are in clinical trials and preclinical pipeline. The review focuses on three therapeutic areas including treatments of cancer, tuberculosis, and tobacco cessation. Alkaloid scaffolds in drugs and leads are inspired by those of naturally occurring alkaloids, and these scaffolds include pyridine, piperidine, quinoline, quinolinone, quinazoline, isoquinoline, indole, indolinone, isoindole, isoxazole, imidazole, indazole, thiazole, pyrazole, oxazolidinone, oxadiazole, and benzazepine. In addition to medicinal chemistry aspects, natural products possessing an individual alkaloid scaffold, as well as the mechanism of action of drugs and leads, are also discussed in this review.

Activity ranking of synthetic analogs targeting vascular endothelial growth factor receptor 2 by an integrated cell membrane chromatography system.

PubMed

Wang, Dongyao; Lv, Diya; Chen, Xiaofei; Liu, Yue; Ding, Xuan; Jia, Dan; Chen, Langdong; Zhu, Zhenyu; Cao, Yan; Chai, Yifeng

2015-12-01

Evaluating the biological activities of small molecules represents an important part of the drug discovery process. Cell membrane chromatography (CMC) is a well-developed biological chromatographic technique. In this study, we have developed combined SMMC-7721/CMC and HepG2/CMC with high-performance liquid chromatography and time-of-flight mass spectrometry to establish an integrated screening platform. These systems was subsequently validated and used for evaluating the activity of quinazoline compounds, which were designed and synthesized to target vascular endothelial growth factor receptor 2. The inhibitory activities of these compounds towards this receptor were also tested using a classical caliper mobility shift assay. The results revealed a significant correlation between these two methods (R(2) = 0.9565 or 0.9420) for evaluating the activities of these compounds. Compared with traditional methods of evaluating the activities analogous compounds, this integrated cell membrane chromatography screening system took less time and was more cost effective, indicating that it could be used as a practical method in drug discovery. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Integrated CO2 capture-fixation chemistry via interfacial ionic liquid catalyst in laminar gas/liquid flow.

PubMed

Vishwakarma, Niraj K; Singh, Ajay K; Hwang, Yoon-Ho; Ko, Dong-Hyeon; Kim, Jin-Oh; Babu, A Giridhar; Kim, Dong-Pyo

2017-03-06

Simultaneous capture of carbon dioxide (CO 2 ) and its utilization with subsequent work-up would significantly enhance the competitiveness of CO 2 -based sustainable chemistry over petroleum-based chemistry. Here we report an interfacial catalytic reaction platform for an integrated autonomous process of simultaneously capturing/fixing CO 2 in gas-liquid laminar flow with subsequently providing a work-up step. The continuous-flow microreactor has built-in silicon nanowires (SiNWs) with immobilized ionic liquid catalysts on tips of cone-shaped nanowire bundles. Because of the superamphiphobic SiNWs, a stable gas-liquid interface maintains between liquid flow of organoamines in upper part and gas flow of CO 2 in bottom part of channel. The intimate and direct contact of the binary reagents leads to enhanced mass transfer and facilitating reactions. The autonomous integrated platform produces and isolates 2-oxazolidinones and quinazolines-2,4(1H,3H)-diones with 81-97% yields under mild conditions. The platform would enable direct CO 2 utilization to produce high-valued specialty chemicals from flue gases without pre-separation and work-up steps.

Integrated CO2 capture-fixation chemistry via interfacial ionic liquid catalyst in laminar gas/liquid flow

PubMed Central

Vishwakarma, Niraj K.; Singh, Ajay K.; Hwang, Yoon-Ho; Ko, Dong-Hyeon; Kim, Jin-Oh; Babu, A. Giridhar; Kim, Dong-Pyo

2017-01-01

Simultaneous capture of carbon dioxide (CO2) and its utilization with subsequent work-up would significantly enhance the competitiveness of CO2-based sustainable chemistry over petroleum-based chemistry. Here we report an interfacial catalytic reaction platform for an integrated autonomous process of simultaneously capturing/fixing CO2 in gas–liquid laminar flow with subsequently providing a work-up step. The continuous-flow microreactor has built-in silicon nanowires (SiNWs) with immobilized ionic liquid catalysts on tips of cone-shaped nanowire bundles. Because of the superamphiphobic SiNWs, a stable gas–liquid interface maintains between liquid flow of organoamines in upper part and gas flow of CO2 in bottom part of channel. The intimate and direct contact of the binary reagents leads to enhanced mass transfer and facilitating reactions. The autonomous integrated platform produces and isolates 2-oxazolidinones and quinazolines-2,4(1H,3H)-diones with 81–97% yields under mild conditions. The platform would enable direct CO2 utilization to produce high-valued specialty chemicals from flue gases without pre-separation and work-up steps. PMID:28262667

Discovery of Novel, Highly Potent, and Selective Matrix Metalloproteinase (MMP)-13 Inhibitors with a 1,2,4-Triazol-3-yl Moiety as a Zinc Binding Group Using a Structure-Based Design Approach.

PubMed

Nara, Hiroshi; Kaieda, Akira; Sato, Kenjiro; Naito, Takako; Mototani, Hideyuki; Oki, Hideyuki; Yamamoto, Yoshio; Kuno, Haruhiko; Santou, Takashi; Kanzaki, Naoyuki; Terauchi, Jun; Uchikawa, Osamu; Kori, Masakuni

2017-01-26

On the basis of a superposition study of X-ray crystal structures of complexes of quinazoline derivative 1 and triazole derivative 2 with matrix metalloproteinase (MMP)-13 catalytic domain, a novel series of fused pyrimidine compounds which possess a 1,2,4-triazol-3-yl group as a zinc binding group (ZBG) was designed. Among the herein described and evaluated compounds, 31f exhibited excellent potency for MMP-13 (IC 50 = 0.036 nM) and selectivities (greater than 1,500-fold) over other MMPs (MMP-1, -2, -3, -7, -8, -9, -10, and -14) and tumor necrosis factor-α converting enzyme (TACE). Furthermore, the inhibitor was shown to protect bovine nasal cartilage explants against degradation induced by interleukin-1 and oncostatin M. In this article, we report the discovery of extremely potent, highly selective, and orally bioavailable fused pyrimidine derivatives that possess a 1,2,4-triazol-3-yl group as a novel ZBG for selective MMP-13 inhibition.

Discovery of novel, highly potent, and selective quinazoline-2-carboxamide-based matrix metalloproteinase (MMP)-13 inhibitors without a zinc binding group using a structure-based design approach.

PubMed

Nara, Hiroshi; Sato, Kenjiro; Naito, Takako; Mototani, Hideyuki; Oki, Hideyuki; Yamamoto, Yoshio; Kuno, Haruhiko; Santou, Takashi; Kanzaki, Naoyuki; Terauchi, Jun; Uchikawa, Osamu; Kori, Masakuni

2014-11-13

Matrix metalloproteinase-13 (MMP-13) has been implicated to play a key role in the pathology of osteoarthritis. On the basis of X-ray crystallography, we designed a series of potent MMP-13 selective inhibitors optimized to occupy the distinct deep S1' pocket including an adjacent branch. Among them, carboxylic acid inhibitor 21k exhibited excellent potency and selectivity for MMP-13 over other MMPs. An effort to convert compound 21k to the mono sodium salt 38 was promising in all animal species studied. Moreover, no overt toxicity was observed in a preliminary repeat dose oral toxicity study of compound 21k in rats. A single oral dose of compound 38 significantly reduced degradation products (CTX-II) released from articular cartilage into the joint cavity in a rat MIA model in vivo. In this article, we report the discovery of highly potent, selective, and orally bioavailable MMP-13 inhibitors as well as their detailed structure-activity data.

Use of molecular modeling aided design to dial out hERG liability in adenosine A(2A) receptor antagonists.

PubMed

Deng, Qiaolin; Lim, Yeon-Hee; Anand, Rajan; Yu, Younong; Kim, Jae-hun; Zhou, Wei; Zheng, Junying; Tempest, Paul; Levorse, Dorothy; Zhang, Xiaoping; Greene, Scott; Mullins, Deborra; Culberson, Chris; Sherborne, Brad; Parker, Eric M; Stamford, Andrew; Ali, Amjad

2015-08-01

Molecular modeling was performed on a triazolo quinazoline lead compound to help develop a series of adenosine A2A receptor antagonists with improved hERG profile. Superposition of the lead compound onto MK-499, a benchmark hERG inhibitor, combined with pKa calculations and measurement, identified terminal fluorobenzene to be responsible for hERG activity. Docking of the lead compound into an A2A crystal structure suggested that this group is located at a flexible, spacious, and solvent-exposed opening of the binding pocket, making it possible to tolerate various functional groups. Transformation analysis (MMP, matched molecular pair) of in-house available experimental data on hERG provided suggestions for modifications in order to mitigate this liability. This led to the synthesis of a series of compounds with significantly reduced hERG activity. The strategy used in the modeling work can be applied to other medicinal chemistry programs to help improve hERG profile. Copyright © 2015 Elsevier Ltd. All rights reserved.

Protozoan Parasite Growth Inhibitors Discovered by Cross-Screening Yield Potent Scaffolds for Lead Discovery

PubMed Central

2015-01-01

Tropical protozoal infections are a significant cause of morbidity and mortality worldwide; four in particular (human African trypanosomiasis (HAT), Chagas disease, cutaneous leishmaniasis, and malaria) have an estimated combined burden of over 87 million disability-adjusted life years. New drugs are needed for each of these diseases. Building on the previous identification of NEU-617 (1) as a potent and nontoxic inhibitor of proliferation for the HAT pathogen (Trypanosoma brucei), we have now tested this class of analogs against other protozoal species: T. cruzi (Chagas disease), Leishmania major (cutaneous leishmaniasis), and Plasmodium falciparum (malaria). Based on hits identified in this screening campaign, we describe the preparation of several replacements for the quinazoline scaffold and report these inhibitors’ biological activities against these parasites. In doing this, we have identified several potent proliferation inhibitors for each pathogen, such as 4-((3-chloro-4-((3-fluorobenzyl)oxy)phenyl)amino)-6-(4-((4-methyl-1,4-diazepan-1-yl)sulfonyl)phenyl)quinoline-3-carbonitrile (NEU-924, 83) for T. cruzi and N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-7-(4-((4-methyl-1,4-diazepan-1-yl)sulfonyl)phenyl)cinnolin-4-amine (NEU-1017, 68) for L. major and P. falciparum. PMID:26087257

Inhibitory activity of tryptanthrin on prostaglandin and leukotriene synthesis.

PubMed

Danz, Henning; Stoyanova, Stefka; Thomet, Olivier A R; Simon, Hans-Uwe; Dannhardt, Gerd; Ulbrich, Holger; Hamburger, Matthias

2002-10-01

The indolo[2,1- b]quinazoline alkaloid tryptanthrin has previously been identified as the cyclooxygenase-2 (COX-2) inhibitory principle in the extract ZE550 prepared from the medicinal plant Isatis tinctoria (Brassicaceae). We here investigated the potential inhibitory activity of tryptanthrin and ZE550 on COX-2, COX-1 in cellular and cell-free systems. A certain degree of selectivity towards COX-2 was observed when COX-1-dependent formation of thromboxane B(2) (TxB(2)) in HEL cells and COX-2-dependent formation of 6-ketoprostaglandin F(1alpha) (6-keto-PGF(1alpha)) in Mono Mac 6 and RAW 264.7 cells were compared. Preferential inhibition of COX-2 by two orders of magnitude was found in phorbol myristate acetate (PMA) activated bovine aortic coronary endothelial cells (BAECs). Assays with purified COX isoenzymes from sheep confirmed the high selectivity towards COX-2. The leukotriene B(4) (LTB(4)) release from calcium ionophore-stimulated human granulocytes (neutrophils) was used as a model to determine 5-lipoxygenase (5-LOX) activity. Tryptanthrin and the extract ZE550 inhibited LTB(4) release in a dose dependent manner and with a potency comparable to that of the clinically used 5-LOX inhibitor zileuton.

Pyridinylquinazolines Selectively Inhibit Human Methionine Aminopeptidase-1 in Cells

PubMed Central

Zhang, Feiran; Bhat, Shridhar; Gabelli, Sandra B.; Chen, Xiaochun; Miller, Michelle S.; Nacev, Benjamin A.; Cheng, Yim Ling; Meyers, David J.; Tenney, Karen; Shim, Joong Sup; Crews, Phillip; Amzel, L. Mario; Ma, Dawei; Liu, Jun O.

2013-01-01

Methionine aminopeptidases (MetAPs) which remove the initiator methionine from nascent peptides are essential in all organisms. While MetAP2 has been demonstrated to be a therapeutic target for inhibiting angiogenesis in mammals, MetAP1 seems to be vital for cell proliferation. Our earlier efforts identified two structural classes of human MetAP1 (HsMetAP1)-selective inhibitors (1–4). But all of them failed to inhibit cellular HsMetAP1. Using Mn(II) or Zn(II) to activate HsMetAP1, we found that 1–4 could only effectively inhibit purified HsMetAP1 in the presence of physiologically unachievable concentrations of Co(II). In an effort to seek Co(II)-independent inhibitors, a novel structural class containing a 2-(pyridin-2-yl)quinazoline core has been discovered. Many compounds in this class potently and selectively inhibited HsMetAP1 without Co(II). Subsequently, we demonstrated that 11j, an auxiliary metal-dependent inhibitor, effectively inhibited HsMetAP1 in primary cells. This is the first report that an HsMetAP1-selective inhibitor is effective against its target in cells. PMID:23634668

Synthesis and evaluation of quinazoline amino acid derivatives as mono amine oxidase (MAO) inhibitors.

PubMed

Khattab, Sherine Nabil; Haiba, Nesreen Saied; Asal, Ahmed Mosaad; Bekhit, Adnan A; Amer, Adel; Abdel-Rahman, Hamdy M; El-Faham, Ayman

2015-07-01

A series of quinazolinone amino acid ester and quinazolinone amino acid hydrazides were prepared under microwave irradiation as well as conventional condition. The microwave irradiation afforded the product in less reaction time, higher yield and purity. The structures of the synthesized compounds were confirmed by IR, NMR, and elemental analysis. The new synthesized compounds were studied for their monoamine oxidase inhibitory activity. They showed more selective inhibitory activity toward MAO-A than MAO-B. Compounds 7, 10, and 15 showed MAO-A inhibition activity (IC50=3.6×10(-9), 2.8×10(-9), 2.1×10(-9) M, respectively) comparable to that of the standard clorgyline (IC50=2.9×10(-9)M). 2-(2-(Benzo[d][1,3]dioxol-5-yl)-4-oxo-1,2-dihydroquinazolin-3(4H)-yl)acetohydrazide 15 showed selective MAO-A inhibition activity (SI=39524) superior to that of the standard clorgyline (SI=33793). The acute toxicity of the synthesized compounds was determined. In addition, computer-assisted simulated docking experiments were performed to rationalize the biological activity. Copyright © 2015 Elsevier Ltd. All rights reserved.

Discovery and evaluation of triple inhibitors of VEGFR-2, TIE-2 and EphB4 as anti-angiogenic and anti-cancer agents

PubMed Central

Zhang, Lin; Shan, Yuanyuan; Ji, Xingyue; Zhu, Mengyuan; Li, Chuansheng; Sun, Ying; Si, Ru; Pan, Xiaoyan; Wang, Jinfeng; Ma, Weina; Dai, Bingling; Wang, Binghe; Zhang, Jie

2017-01-01

Receptor tyrosine kinases (RTKs), especially VEGFR-2, TIE-2, and EphB4, play a crucial role in both angiogenesis and tumorigenesis. Moreover, complexity and heterogeneity of angiogenesis make it difficult to treat such pathological traits with single-target agents. Herein, we developed two classes of multi-target RTK inhibitors (RTKIs) based on the highly conserved ATP-binding pocket of VEGFR-2/TIE-2/EphB4, using previously reported BPS-7 as a lead compound. These multi-target RTKIs exhibited considerable potential as novel anti-angiogenic and anticancer agents. Among them, QDAU5 displayed the most promising potency and selectivity. It significantly suppressed viability of EA.hy926 and proliferation of several cancer cells. Further investigations indicated that QDAU5 showed high affinity to VEGFR-2 and reduced the phosphorylation of VEGFR-2. We identified QDAU5 as a potent multiple RTKs inhibitor exhibiting prominent anti-angiogenic and anticancer potency both in vitro and in vivo. Moreover, quinazolin-4(3H)-one has been identified as an excellent hinge binding moiety for multi-target inhibitors of angiogenic VEGFR-2, Tie-2, and EphB4. PMID:29285210

Inhibition of cell signaling by the combi-nitrosourea FD137 in the androgen independent DU145 prostate cancer cell line.

PubMed

Qiu, Qiyu; Dudouit, Fabienne; Banerjee, Ranjita; McNamee, James P; Jean-Claude, Bertrand J

2004-04-01

FD137, a nitrosourea appended to a quinazoline ring, was designed to simultaneously block epidermal growth factor receptor (EGFR)-mediated signaling and damage genomic DNA in refractory EGF-dependent prostate tumors. The mixed inhibition of cell signaling and DNA damage by FD137 were determined by Western blotting, RT-PCR, flow cytometry, sulforhodamine B (SRB), and comet assay. FD137 and its metabolite FD110 induced a dose-dependent increase in inhibition of EGF-stimulated EGFR autophosphorylation and this translated into blockade of c-fos gene expression in DU145 cells. FD137 induced significant levels of DNA damage and showed 150-fold greater anti-proliferative activity than BCNU, a classical nitrosourea. In contrast to BCNU, complete inhibition of EGF-induced cell transition to S-phase was observed at concentrations of FD137 as low as 3 microM. FD137 could not only damage DNA, but also significantly block downstream EGFR-mediated signaling. The superior activity of FD137 may be imputable to the combined effect of its mixed EGFR/DNA targeting properties. This novel strategy may well represent a new approach to target nitrosoureas to EGFR-overexpressing carcinomas of the prostate. Copyright 2004 Wiley-Liss, Inc.

Pulsed corona discharge oxidation of aqueous carbamazepine micropollutant.

PubMed

Ajo, Petri; Krzymyk, Ewelina; Preis, Sergei; Kornev, Iakov; Kronberg, Leif; Louhi-Kultanen, Marjatta

2016-08-01

The anti-epileptic drug carbamazepine (CBZ) receives growing attention due to slow biodegradation and inherent accumulation in the aquatic environment. The application of a gas-phase pulsed corona discharge (PCD) was investigated to remove CBZ from synthetic solutions and spiked wastewater effluent from a municipal wastewater treatment facility. The treated water was showered between high voltage (HV) wires and grounded plate electrodes, to which ultra-short HV pulses were applied. CBZ was readily oxidized and 1-(2-benzaldehyde)-4-hydroquinazoline-2-one (BQM) and 1-(2-benzaldehyde)-4-hydro-quinazoline-2,4-dione (BQD) were identified as the most abundant primary transformation products, which, contrary to CBZ ozonation data available in the literature, were further easily oxidized with PCD: BQM and BQD attributed to only a minor portion of the target compound oxidized. In concentrations commonly found in wastewater treatment plant effluents (around 5 µg L(-1)), up to 97% reduction in CBZ concentration was achieved at mere 0.3 kW h m(-3) energy consumption, and over 99.9% was removed at 1 kW h m(-3). The PCD application proved to be efficient in the removal of both the parent substance and its known transformation products, even with the competing reactions in the complex composition of wastewater.

Design, synthesis and biological evaluation of novel quinazoline-2,4-diones conjugated with different amino acids as potential chitin synthase inhibitors.

PubMed

Noureldin, Nada A; Kothayer, Hend; Lashine, El-Sayed M; Baraka, Mohamed M; Huang, Yanrong; Li, Bing; Ji, Qinggang

2018-05-25

A series of (2-(1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl) acetamido) acids) (6 a-m), (7) has been designed to inhibit the action of fungus chitin synthase enzyme (CHS). The synthesis of the designed compounds was carried out in four steps starting from the reaction between 1-methylquinazoline-2,4(1H,3H)-dione and ethyl chloroacetate to yield the ethyl acetate derivative. This ester was hydrolyzed to the corresponding carboxylic acid derivative that was then utilized to couple several amino acids getting the final designed compounds. The synthesized compounds were tested for their inhibition against CHS. Compound 7 showed the highest potency among others with minimum inhibitory concentration (IC 50 ) of 0.166 mmol/L, while polyoxin B (the positive control) had IC 50 of 0.17 mmol/L. The synthesized compounds were also evaluated for their in vitro antifungal activity using Aspergillus fumigates, Aspergillus flavus, Crytococcus neoformans and Candida albicans. Unfortunately, the 14 synthesized compounds showed lower in vitro activity compared to the used active controls. However, compound 6m and fluconazole have synergistic effect on Aspergillus flavus; Compounds 7 and fluconazole have synergistic effects on Aspergillus fumigates. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Structure and evaluation of antibacterial and antitubercular properties of new basic and heterocyclic 3-formylrifamycin SV derivatives obtained via 'click chemistry' approach.

PubMed

Pyta, Krystian; Klich, Katarzyna; Domagalska, Joanna; Przybylski, Piotr

2014-09-12

Thirty four novel derivatives of 3-formylrifamycin SV were synthesized via reductive alkylation and copper(I)-catalysed azide-alkyne cycloaddition. According to the obtained results, 'click chemistry' can be successfully applied for modification of structurally complex antibiotics such as rifamycins, with the formation of desired 1,2,3-triazole products. However, when azide-alkyne cycloaddition on 3-formylrifamycin SV derivatives demanded higher amount of catalyst, lower temperature and longer reaction time because of the high volatility of substrates, an unexpected intramolecular condensation with the formation of 3,4-dihydrobenzo[g]quinazoline heterocyclic system took place. Structures of new derivatives in solution were determined using one- and two-dimensional NMR methods and FT-IR spectroscopy. Computational DFT and PM6 methods were employed to correlate their conformation and acid-base properties to biological activity and establish SAR of the novel compounds. Microbiological, physico-chemical (logP, solubility) and structural studies of newly synthesised rifamycins indicated that for the presence of relatively high antibacterial (MIC ~0.01 nmol/mL) and antitubercular (MIC ~0.006 nmol/mL) activities, a rigid and basic substituent at C(3) arm, containing a protonated nitrogen atom "open" toward intermolecular interactions, is required. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Quinazolinones-Phenylquinoxaline hybrids with unsaturation/saturation linkers as novel anti-proliferative agents.

PubMed

Palem, Jyothsna Devi; Alugubelli, Gopi Reddy; Bantu, Rajashaker; Nagarapu, Lingaiah; Polepalli, Sowjanya; Jain, S Nishanth; Bathini, Raju; Manga, Vijjulatha

2016-07-01

A new series of novel quinazolinones with allylphenyl quinoxaline hybrids 9a-n were efficiently synthesized in good yields by the reaction of 3-allyl-2-methylquinazolin-4(3H)-one (5a-n) with bromophenyl)quinoxaline (8) utilizing Pd catalyzed Heck-cross coupling and evaluated for anti-proliferative activity against four cancer cell lines such as HeLa (cervical), MIAPACA (pancreatic), MDA-MB-231 (breast) and IMR32 (neuroblastoma). Compounds 9a, 9e, 9g and 9h exhibited promising anti-proliferative activity with GI50 values ranging from 0.06 to 0.2μM against four cell lines, while compounds 9e and 9k showed significant activity against HeLa and MIAPACA cell lines and compounds 9b, 9d, 9h and 9j showed selective potency against IMR32 and MDA-MB-231 cell lines. This is the first report on the synthesis and in vitro anti-proliferative evaluation of E-2-(4-substituted)-3-(3-(4-(quinoxalin-2-yl)phenyl)allyl)quinazolin-4(3H)-ones (9a-n). Docking results indicate a sign of good correlation between experimental activity and calculated binding affinity (dock score), suggesting that these compounds could act as promising DNA intercalates. Copyright © 2016 Elsevier Ltd. All rights reserved.

Metabolite characterization of a novel anti-cancer agent, icotinib, in humans through liquid chromatography/quadrupole time-of-flight tandem mass spectrometry.

PubMed

Liu, Dongyang; Jiang, Ji; Zhang, Li; Tan, Fenlai; Wang, Yingxiang; Hu, Pei

2011-08-15

Icotinib is a novel anti-cancer drug that has shown promising clinical efficacy and safety in patients with non-small-cell lung cancer (NSCLC). At this time, the metabolic fate of icotinib in humans is unknown. In the present study, a liquid chromatography/quadrupole time-of-flight tandem mass spectrometry (LC/Q-TOF MS) method was established to characterize metabolites of icotinib in human plasma, urine and feces. In addition, nuclear magnetic resonance (NMR) detection was utilized to determine the connection between side-chain and quinazoline groups for some complex metabolites. In total, 29 human metabolites (21 isomer metabolites) were characterized, of which 23 metabolites are novel compared to the metabolites in rats. This metabolic study revealed that icotinib was extensively metabolized at the 12-crown-4 ether moiety (ring-opening and further oxidation), carbon 15 (hydroxylation) and an acetylene moiety (oxidation) to yield 19 oxidized metabolites and to further form 10 conjugates with sulfate acid or glucuronic acid. To our knowledge, this is the first report of the human metabolic profile of icotinib. Study results indicated that significant attention should be paid to the metabolic profiles of NSCLC patients during the development of icotinib. Copyright © 2011 John Wiley & Sons, Ltd.

Icotinib: activity and clinical application in Chinese patients with lung cancer.

PubMed

Guan, Yong-Song; He, Qing; Li, Mei

2014-04-01

Icotinib (BPI-2009H, Conmana) is a novel oral quinazoline compound that has proven survival benefit in Chinese patients with lung cancer, for which several therapies are currently available often with unsatisfactory results. Icotinib is the first self-developed small molecular drug in China for targeted therapy of lung cancer. The authors' experience in the clinical application of icotinib is reviewed in combination with related publications in the literature. Antitumor activities were observed in non-small-cell lung cancer and others in several recent studies. On 7 June 2011, icotinib was approved by the State Food and Drug Administration of China for the treatment of local advanced or metastatic non-small-cell lung cancer based on the results of a nationwide, of 27 centers, randomized, double-blind, double-modulated, parallel-controlled, Phase III trial with single agent icotinib in lung cancer patients after failure of chemotherapy. Icotinib is a generic drug. Compared to the other two commercially available EGFR tyrosine kinase inhibitors, gefitinib and erlotinib, icotinib is similar to them in chemical structure, mechanism of activity and therapeutic effects but less expensive. Better safety as well as a wider therapeutic window has also been proven in several Chinese studies. Future studies on cost effectiveness are warranted.

Vibrational spectroscopic (FT-IR and FT-Raman) studies, HOMO-LUMO, NBO analysis and MEP of 6-methyl-1-({[(2E)-2-methyl-3-phenyl-prop-2-en-1-yl]oxy}methyl)-1,2,3,4-tetra-hydroquinazoline-2,4-dione, a potential chemotherapeutic agent, using density functional methods.

PubMed

Sebastian, Sr S H Roseline; Al-Tamimi, Abdul-Malek S; El-Brollosy, Nasser R; El-Emam, Ali A; Yohannan Panicker, C; Van Alsenoy, Christian

2015-01-05

6-Methyl-1-({[(2E)-2-methyl-3-phenyl-prop-2-en-1-yl]oxy}methyl)-1,2,3,4-tetra-hydro quinazoline-2,4-dione was prepared via treatment of silylated 6-methylquinazoline-2,4-dione with bis-[(E)-2-methyl-3-phenylallyloxy]methane. FT-IR and FT-Raman spectra were recorded and analyzed. The vibrational wavenumbers were computed using DFT methods and are assigned with the help of potential energy distribution method. The first hyperpolarizability, infrared intensities and Raman activities also reported. The geometrical parameters of the title compound obtained from XRD studies are in agreement with the calculated (B3LYP) values. The stability of the molecule arising from hyper-conjugative interaction and charge delocalization has been analyzed using NBO analysis. The HOMO and LUMO analysis are used to determine the charge transfer within the molecule. MEP was performed by the B3LYP method and from the MEP it is evident that the negative charge covers the CO group and the positive region is over the phenyl ring and NH group. Copyright © 2014 Elsevier B.V. All rights reserved.

Combined 3D-QSAR and molecular docking study on 7,8-dialkyl-1,3-diaminopyrrolo-[3,2-f] Quinazoline series compounds to understand the binding mechanism of DHFR inhibitors

NASA Astrophysics Data System (ADS)

Aouidate, Adnane; Ghaleb, Adib; Ghamali, Mounir; Chtita, Samir; Choukrad, M'barek; Sbai, Abdelouahid; Bouachrine, Mohammed; Lakhlifi, Tahar

2017-07-01

A series of nineteen DHFR inhibitors was studied based on the combination of two computational techniques namely, three-dimensional quantitative structure activity relationship (3D-QSAR) and molecular docking. The comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) were developed using 19 molecules having pIC50 ranging from 9.244 to 5.839. The best CoMFA and CoMSIA models show conventional determination coefficients R2 of 0.96 and 0.93 as well as the Leave One Out cross-validation determination coefficients Q2 of 0.64 and 0.72, respectively. The predictive ability of those models was evaluated by the external validation using a test set of five compounds with predicted determination coefficients R2test of 0.92 and 0.94, respectively. The binding mode between this kind of compounds and the DHFR enzyme in addition to the key amino acid residues were explored by molecular docking simulation. Contour maps and molecular docking identified that the R1 and R2 natures at the pyrazole moiety are the important features for the optimization of the binding affinity to the DHFR receptor. According to the good concordance between the CoMFA/CoMSIA contour maps and docking results, the obtained information was explored to design novel molecules.

Behavioural and electrophysiological responses of Triatoma dimidiata nymphs to conspecific faecal volatiles.

PubMed

Galvez-Marroquin, Z; Cruz-López, L; Malo, E A; Ramsey, J M; Rojas, J C

2018-03-01

The behavioural and electrophysiological (electroantennography) responses of the first two instars of Triatoma dimidiata (Hemiptera: Reduviidae) Latreille to fresh and dry faecal headspace volatile extracts from fifth instar conspecific nymphs and synthetic compounds were analysed in this study. Recently emerged nymphs (3-5 days) aggregated around filter paper impregnated with dry faeces and around filter paper impregnated with extracts from both fresh and dry faeces. Older first instars (10-15 days) and second instars aggregated around filter paper impregnated with fresh and dry faeces, and their respective headspace extracts. Dry faecal volatile extracts elicited the strongest antennal responses, followed by fresh faecal extracts. Gas chromatography-mass spectrometry analysis of dried faecal headspace volatiles demonstrated the presence of 12 compounds: 2-ethyl-1-hexanol, 1,2,4-trimethylbenzene, n-octadecane, n-nonadecane, n-eicosane, n-heneicosane, n-tricosane, n-pentaeicosane, n-hexaeicosane, n-octaeicosane, nonanal, and 4-methyl quinazoline. In fresh faecal headspace extracts, only nonanal was clearly detected, although there were other trace compounds, including several unidentified sesquiterpenes. Four of the 11 compounds tested individually elicited aggregation behaviour at concentrations of 100 ng/µL and 1 µg/µL. A blend containing these four components also mediated the aggregation of nymphs. These volatiles may be valuable for developing monitoring methods and designing sensitive strategies to detect and measure T. dimidiata infestation. © 2017 The Royal Entomological Society.

Electrochemical investigation on the corrosion inhibition of mild steel by Quinazoline Schiff base compounds in hydrochloric acid solution.

PubMed

Khan, Ghulamullah; Basirun, Wan Jeffrey; Kazi, Salim Newaz; Ahmed, Pervaiz; Magaji, Ladan; Ahmed, Syed Muzamil; Khan, Ghulam Mustafa; Rehman, Muhammad Abdur; Badry, Ahmad Badarudin Bin Mohamad

2017-09-15

The inhibitory effect of two Schiff bases 3-(5-methoxy-2-hydroxybenzylideneamino)-2-(-5-methoxy-2-hydroxyphenyl)-2,3-dihydroquinazoline-4(1H)-one (MMDQ), and 3-(5-nitro-2-hydroxybenzylideneamino)-2(5-nitro-2-hydroxyphenyl)-2,3-dihydroquinazoline-4(1H)-one (NNDQ) on the corrosion of mild steel in 1M hydrochloric acid were studied using mass loss, potentiodynamic polarization technique and electrochemical impedance spectroscopy measurements at ambient temperature. The investigation results indicate that the Schiff Bases compounds with an average efficiency of 92% at 1.0mM of additive concentration have fairly effective inhibiting properties for mild steel in hydrochloric acid, and acts as mixed type inhibitor character. The inhibition efficiencies measured by all measurements show that the inhibition efficiencies increase with increase in inhibitor concentration. This reveals that the inhibitive mechanism of inhibitors were primarily due to adsorption on mild steel surface, and follow Langmuir adsorption isotherm. The temperature effect on the inhibition process in 1MHCl with the addition of investigated Schiff bases was studied at a temperature range of 30-60°C, and the activation parameters (Ea, ΔH and ΔS) were calculated to elaborate the corrosion mechanism. The differences in efficiency for two investigated inhibitors are associated with their chemical structures. Copyright © 2017 Elsevier Inc. All rights reserved.

Synthesis, crystal structure determination, biological screening and docking studies of N1-substituted derivatives of 2,3-dihydroquinazolin-4(1H)-one as inhibitors of cholinesterases.

PubMed

Sultana, Nargis; Sarfraz, Muhammad; Tanoli, Saba Tahir; Akram, Muhammad Safwan; Sadiq, Abdul; Rashid, Umer; Tariq, Muhammad Ilyas

2017-06-01

Pursuing the strategy of developing potent AChE inhibitors, we attempted to carry out the N 1 -substitution of 2,3-dihydroquinazolin-4(1H)-one core. A set of 32 N-alkylated/benzylated quinazoline derivatives were synthesized, characterized and evaluated for their inhibition against cholinesterases. N-alkylation of the series of the compounds reported previously (N-unsubstituted) resulted in improved activity. All the compounds showed inhibition of both enzymes in the micromolar to submicromolar range. Structure activity relationship (SAR) of the 32 derivatives showed that N-benzylated compounds possess good activity than N-alkylated compounds. N-benzylated compounds 2ad and 2af were found very active with their IC 50 values toward AChE in submicromolar range (0.8µM and 0.6µM respectively). Binding modes of the synthesized compounds were explored by using GOLD (Genetic Optimization for Ligand Docking) suit v5.4.1. Computational predictions of ADMET studies reveal that all the compounds have good pharmacokinetic properties with no AMES toxicity and carcinogenicity. Moreover, all the compounds are predicted to be absorbed in human intestine and also have the ability to cross blood brain barrier. Overall, the synthesized compounds have established a structural foundation for the design of new inhibitors of cholinesterase. Copyright © 2017 Elsevier Inc. All rights reserved.

Spectral Characterization and 3D Molecular Modeling Studies of Metal Complexes Involving the O, N-Donor Environment of Quinazoline-4(3H)-one Schiff Base and Their Biological Studies

PubMed Central

Siddappa, Kuruba; Mane, Sunilkumar B.

2014-01-01

A simple condensation of 3-amino-2-methylquinazoline-4-one with 2-hydroxy-1-naphthaldehyde produced new tridentate ONO donor Schiff base ligand with efficient yield. The structural characterization of ligand and its Cu(II), Ni(II), Co(II), Mn(II), Zn(II), and Cd(II) complexes were achieved by the aid of elemental analysis, spectral characterization such as (UV-visible, IR, NMR, mass, and ESR), and magnetic data. The analytical and spectroscopic studies suggest the octahedral geometries of Cu(II), Co(II), Ni(II) and Mn(II) complexes and tetrahedral geometry of Zn(II) and Cd(II) complexes with the tridentate ONO Schiff base ligand. Furthermore, the conclusions drawn from these studies afford further support to the mode of bonding discussed on the basis of their 3D molecular modeling studies by considering different bond lengths, bond angles, and bond distance. The ligand and its metal complexes evaluated for their antimicrobial activity against Staphylococcus aureus (MTCC number 7443), Bacillus subtilis (MTCC number 9878), Escherichia coli (MTCC number 1698), Aspergillus niger (MTCC number 281), and Aspergillus flavus (MTCC number 277). The MIC of these compounds was found to be most active at 10 μg/mL concentration in inhibiting the growth of the tested organisms. The DNA cleavage activity of all the complexes was studied by gel electrophoresis method. PMID:24678278

Synthesis and in vitro anti-proliferative activity of some novel isatins conjugated with quinazoline/phthalazine hydrazines against triple-negative breast cancer MDA-MB-231 cells as apoptosis-inducing agents.

PubMed

Eldehna, Wagdy M; Almahli, Hadia; Al-Ansary, Ghada H; Ghabbour, Hazem A; Aly, Mohamed H; Ismael, Omnia E; Al-Dhfyan, Abdullah; Abdel-Aziz, Hatem A

2017-12-01

Treatment of patients with triple-negative breast cancer (TNBC) is challenging due to the absence of well- defined molecular targets and the heterogeneity of such disease. In our endeavor to develop potent isatin-based anti-proliferative agents, we utilized the hybrid-pharmacophore approach to synthesize three series of novel isatin-based hybrids 5a-h, 10a-h and 13a-c, with the prime goal of developing potent anti-proliferative agents toward TNBC MDA-MB-231 cell line. In particular, compounds 5e and 10g were the most active hybrids against MDA-MB-231 cells (IC 50  = 12.35 ± 0.12 and 12.00 ± 0.13 μM), with 2.37- and 2.44-fold increased activity than 5-fluorouracil (5-FU) (IC 50  = 29.38 ± 1.24 μM). Compounds 5e and 10g induced the intrinsic apoptotic mitochondrial pathway in MDA-MB-231; evidenced by the reduced expression of the anti-apoptotic protein Bcl-2, the enhanced expression of the pro-apoptotic protein Bax and the up-regulated active caspase-9 and caspase-3 levels. Furthermore, 10g showed significant increase in the percent of annexin V-FITC positive apoptotic cells from 3.88 to 31.21% (8.4 folds compared to control).

Suppression of lipin-1 expression increases monocyte chemoattractant protein-1 expression in 3T3-L1 adipocytes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Takahashi, Nobuhiko, E-mail: ntkhs@hoku-iryo-u.ac.jp; Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, 2-1-1-1 Midorigaoka-Higashi, Asahikawa, Hokkaido 078-8510; Yoshizaki, Takayuki

2011-11-11

Highlights: Black-Right-Pointing-Pointer Lipin-1 affects lipid metabolism, adipocyte differentiation, and transcription. Black-Right-Pointing-Pointer Adipose lipin-1 expression is reduced in obesity. Black-Right-Pointing-Pointer Lipin-1 depletion using siRNA in 3T3-L1 adipocytes increased MCP-1 expression. Black-Right-Pointing-Pointer Lipin-1 is involved in adipose inflammation. -- Abstract: Lipin-1 plays a crucial role in the regulation of lipid metabolism and cell differentiation in adipocytes. Expression of adipose lipin-1 is reduced in obesity, and metabolic syndrome. However, the significance of this reduction remains unclear. This study investigated if and how reduced lipin-1 expression affected metabolism. We assessed mRNA expression levels of various genes related to adipocyte metabolism in lipin-1-depleted 3T3-L1 adipocytesmore » by introducing its specific small interfering RNA. In lipin-1-depleted adipocytes, mRNA and protein expression levels of monocyte chemoattractant protein-1 (MCP-1) were significantly increased, although the other genes tested were not altered. The conditioned media from the cells promoted monocyte chemotaxis. The increase in MCP-1 expression was prevented by treatment with quinazoline or salicylate, inhibitors of nuclear factor-{kappa}B activation. Because MCP-1 is related to adipose inflammation and systemic insulin resistance, these results suggest that a reduction in adipose lipin-1 in obesity may exacerbate adipose inflammation and metabolism.« less

Comparison of biological activities of selenium and silver nanoparticles attached with bioactive phytoconstituents: green synthesized using Spermacoce hispida extract

NASA Astrophysics Data System (ADS)

Vennila, Krishnan; Chitra, Loganathan; Balagurunathan, Rama; Palvannan, Thayumanavan

2018-03-01

Selenium and silver nanoparticles (NPs) were synthesized using Spermacoce hispida aqueous leaf extract (Sh-ALE). The optimum condition required for the synthesis of Sh-SeNPs was found to be 30 mM selenious acid solution to Sh-ALE at the ratio of 4:46, pH 9, incubated at 40 °C for 10 min. On the other hand, for Sh-AgNPs the optimum condition was found to be 1 mM AgNO3 to the Sh-ALE solution at the ratio of 4:46, pH 8, incubated at 40 °C for 10 min. SEM analysis revealed that both the Sh-AgNPs and Sh-SeNPs are predominantly rod-shaped. Sh-SeNPs and Sh-AgNPs were found to possess concentration-dependent antioxidant activity. However, Sh-SeNPs showed potent anti-inflammatory property, antibacterial property and anticancer activity against human cervical cancer cell in comparison to Sh-AgNPs. Phytochemical analysis, FTIR and GC-MS analysis showed that various flavonoids, saponins and phenolic compounds present in Sh-ALE catalysed the formation of NPs. Also, GC-MS analysis revealed that Sh-SeNPs are capped by synaptogenin B and derivatives of apigenin, quinoline and quinazoline. The advantage of attachment of such phytoconstituents on Sh-SeNPs for its potent biological activity in comparison to Sh-AgNPs is evident in in vitro conditions.

Pharmacokinetics and In Vitro Blood-Brain Barrier Screening of the Plant-Derived Alkaloid Tryptanthrin.

PubMed

Jähne, Evelyn A; Eigenmann, Daniela E; Sampath, Chethan; Butterweck, Veronika; Culot, Maxime; Cecchelli, Roméo; Gosselet, Fabien; Walter, Fruzsina R; Deli, Mária A; Smieško, Martin; Hamburger, Matthias; Oufir, Mouhssin

2016-07-01

The indolo[2,1-b]quinazoline alkaloid tryptanthrin was previously identified as a potent anti-inflammatory compound with a unique pharmacological profile. It is a potent inhibitor of cyclooxygenase-2, 5-lipooxygenase-catalyzed leukotriene synthesis, and nitric oxide production catalyzed by the inducible nitric oxide synthase. To characterize the pharmacokinetic properties of tryptanthrin, we performed a pilot in vivo study in male Sprague-Dawley rats (2 mg/kg bw i. v.). Moreover, the ability of tryptanthrin to cross the blood-brain barrier was evaluated in three in vitro human and animal blood-brain barrier models. Bioanalytical UPLC-MS/MS methods used were validated according to current international guidelines. A half-life of 40.63 ± 6.66 min and a clearance of 1.00 ± 0.36 L/h/kg were found in the in vivo pharmacokinetic study. In vitro data obtained with the two primary animal blood-brain barrier models showed a good correlation with an immortalized human monoculture blood-brain barrier model (hBMEC cell line), and were indicative of a high blood-brain barrier permeation potential of tryptanthrin. These findings were corroborated by the in silico prediction of blood-brain barrier penetration. P-glycoprotein interaction of tryptanthrin was assessed by calculation of the efflux ratio in bidirectional permeability assays. An efflux ratio below 2 indicated that tryptanthrin is not subjected to active efflux. Georg Thieme Verlag KG Stuttgart · New York.

Insight into the structural requirements of proton pump inhibitors based on CoMFA and CoMSIA studies.

PubMed

Nayana, M Ravi Shashi; Sekhar, Y Nataraja; Nandyala, Haritha; Muttineni, Ravikumar; Bairy, Santosh Kumar; Singh, Kriti; Mahmood, S K

2008-10-01

In the present study, a series of 179 quinoline and quinazoline heterocyclic analogues exhibiting inhibitory activity against Gastric (H+/K+)-ATPase were investigated using the comparative molecular field analysis (CoMFA) and comparative molecular similarity indices (CoMSIA) methods. Both the models exhibited good correlation between the calculated 3D-QSAR fields and the observed biological activity for the respective training set compounds. The most optimal CoMFA and CoMSIA models yielded significant leave-one-out cross-validation coefficient, q(2) of 0.777, 0.744 and conventional cross-validation coefficient, r(2) of 0.927, 0.914 respectively. The predictive ability of generated models was tested on a set of 52 compounds having broad range of activity. CoMFA and CoMSIA yielded predicted activities for test set compounds with r(pred)(2) of 0.893 and 0.917 respectively. These validation tests not only revealed the robustness of the models but also demonstrated that for our models r(pred)(2) based on the mean activity of test set compounds can accurately estimate external predictivity. The factors affecting activity were analyzed carefully according to standard coefficient contour maps of steric, electrostatic, hydrophobic, acceptor and donor fields derived from the CoMFA and CoMSIA. These contour plots identified several key features which explain the wide range of activities. The results obtained from models offer important structural insight into designing novel peptic-ulcer inhibitors prior to their synthesis.

A chemical potentiator of copper-accumulation used to investigate the iron-regulons of Saccharomyces cerevisiae.

PubMed

Foster, Andrew W; Dainty, Samantha J; Patterson, Carl J; Pohl, Ehmke; Blackburn, Hannah; Wilson, Clare; Hess, Corinna R; Rutherford, Julian C; Quaranta, Laura; Corran, Andy; Robinson, Nigel J

2014-07-01

The extreme resistance of Saccharomyces cerevisiae to copper is overcome by 2-(6-benzyl-2-pyridyl)quinazoline (BPQ), providing a chemical-biology tool which has been exploited in two lines of discovery. First, BPQ is shown to form a red (BPQ)2 Cu(I) complex and promote Ctr1-independent copper-accumulation in whole cells and in mitochondria isolated from treated cells. Multiple phenotypes, including loss of aconitase activity, are consistent with copper-BPQ mediated damage to mitochondrial iron-sulphur clusters. Thus, a biochemical basis of copper-toxicity in S. cerevisiae is analogous to other organisms. Second, iron regulons controlled by Aft1/2, Cth2 and Yap5 that respond to mitochondrial iron-sulphur cluster status are modulated by copper-BPQ causing iron hyper-accumulation via upregulated iron-import. Comparison of copper-BPQ treated, untreated and copper-only treated wild-type and fra2Δ by RNA-seq has uncovered a new candidate Aft1 target-gene (LSO1) and paralogous non-target (LSO2), plus nine putative Cth2 target-transcripts. Two lines of evidence confirm that Fra2 dominates basal repression of the Aft1/2 regulons in iron-replete cultures. Fra2-independent control of these regulons is also observed but CTH2 itself appears to be atypically Fra2-dependent. However, control of Cth2-target transcripts which is independent of CTH2 transcript abundance or of Fra2, is also quantified. Use of copper-BPQ supports a substantial contribution of metabolite repression to iron-regulation. © 2014 The Authors. Molecular Microbiology published by John Wiley & Sons Ltd.

A chemical potentiator of copper-accumulation used to investigate the iron-regulons of Saccharomyces cerevisiae

PubMed Central

Foster, Andrew W; Dainty, Samantha J; Patterson, Carl J; Pohl, Ehmke; Blackburn, Hannah; Wilson, Clare; Hess, Corinna R; Rutherford, Julian C; Quaranta, Laura; Corran, Andy; Robinson, Nigel J

2014-01-01

The extreme resistance of Saccharomyces cerevisiae to copper is overcome by 2-(6-benzyl-2-pyridyl)quinazoline (BPQ), providing a chemical-biology tool which has been exploited in two lines of discovery. First, BPQ is shown to form a red (BPQ)2Cu(I) complex and promote Ctr1-independent copper-accumulation in whole cells and in mitochondria isolated from treated cells. Multiple phenotypes, including loss of aconitase activity, are consistent with copper-BPQ mediated damage to mitochondrial iron–sulphur clusters. Thus, a biochemical basis of copper-toxicity in S. cerevisiae is analogous to other organisms. Second, iron regulons controlled by Aft1/2, Cth2 and Yap5 that respond to mitochondrial iron–sulphur cluster status are modulated by copper-BPQ causing iron hyper-accumulation via upregulated iron-import. Comparison of copper-BPQ treated, untreated and copper-only treated wild-type and fra2Δ by RNA-seq has uncovered a new candidate Aft1 target-gene (LSO1) and paralogous non-target (LSO2), plus nine putative Cth2 target-transcripts. Two lines of evidence confirm that Fra2 dominates basal repression of the Aft1/2 regulons in iron-replete cultures. Fra2-independent control of these regulons is also observed but CTH2 itself appears to be atypically Fra2-dependent. However, control of Cth2-target transcripts which is independent of CTH2 transcript abundance or of Fra2, is also quantified. Use of copper-BPQ supports a substantial contribution of metabolite repression to iron-regulation. PMID:24895027

Linker design for the modular assembly of multifunctional and targeted platinum(ii)-containing anticancer agents.

PubMed

Ding, S; Bierbach, U

2016-08-16

A versatile and efficient modular synthetic platform was developed for assembling multifunctional conjugates and targeted forms of platinum-(benz)acridines, a class of highly cytotoxic DNA-targeted hybrid agents. The synthetic strategy involved amide coupling between succinyl ester-modified platinum compounds (P1, P2) and a set of 11 biologically relevant primary and secondary amines (N1-N11). To demonstrate the feasibility and versatility of the approach, a structurally and functionally diverse range of amines was introduced. These include biologically active molecules, such as rucaparib (a PARP inhibitor), E/Z-endoxifen (an estrogen receptor antagonist), and a quinazoline-based tyrosine kinase inhibitor. Micro-scale reactions in Eppendorf tubes or on 96-well plates were used to screen for optimal coupling conditions in DMF solution with carbodiimide-, uronium-, and phosphonium-based compounds, as well as other common coupling reagents. Reactions with the phosphonium-based coupling reagent PyBOP produced the highest yields and gave the cleanest conversions. Furthermore, it was demonstrated that the chemistry can also be performed in aqueous media and is amenable to parallel synthesis based on multiple consecutive reactions in DMF in a "one-tube" format. In-line LC-MS was used to assess the stability of the conjugates in physiologically relevant buffers. Hydrolysis of the conjugates occurs at the ester moiety and is facilitated by the aquated metal moiety under low-chloride ion conditions. The rate of ester cleavage greatly depends on the nature of the amine component. Potential applications of the linker technology are discussed.

Proliferation-Attenuating and Apoptosis-Inducing Effects of Tryptanthrin on Human Chronic Myeloid Leukemia K562 Cell Line in Vitro

PubMed Central

Miao, Shan; Shi, Xiaopeng; Zhang, Hai; Wang, Siwang; Sun, Jiyuan; Hua, Wei; Miao, Qing; Zhao, Yong; Zhang, Caiqin

2011-01-01

Tryptanthrin, a kind of indole quinazoline alkaloid, has been shown to exhibit anti-microbial, anti-inflammation and anti-tumor effects both in vivo and in vitro. However, its biological activity on human chronic myeloid leukemia cell line K562 is not fully understood. In the present study, we investigated the proliferation-attenuating and apoptosis-inducing effects of tryptanthrin on leukemia K562 cells in vitro and explored the underlying mechanisms. The results showed that tryptanthrin could significantly inhibit K562 cells proliferation in a time- and dose-dependent manner as evidenced by MTT assay and flow cytometry analysis. We also observed pyknosis, chromatin margination and the formation of apoptotic bodies in the presence of tryptanthrin under the electron microscope. Nuclei fragmentation and condensation by Hoechst 33258 staining were detected as well. The amount of apoptotic cells significantly increased whereas the mitochondrial membrane potential decreased dramatically after tryptanthrin exposure. K562 cells in the tryptanthrin treated group exhibited an increase in cytosol cyt-c, Bax and activated caspase-3 expression while a decrease in Bcl-2, mito cyt-c and pro-caspase-3 contents. However, the changes of pro-caspase-3 and activated caspase-3 could be abolished by a pan-caspase inhibitor ZVAD-FMK. These results suggest that tryptanthrin has proliferation-attenuating and apoptosis-inducing effects on K562 cells. The underlying mechanism is probably attributed to the reduction in mitochondria membrane potential, the release of mito cyt-c and pro-caspase-3 activation. PMID:21747710

Mode selectivity in the intramolecular cyclization of ketenimines bearing N-acylimino units: a computational and experimental study.

PubMed

Alajarín, Mateo; Sánchez-Andrada, Pilar; Vidal, Angel; Tovar, Fulgencio

2005-02-18

[reaction: see text] The mode selectivity in the intramolecular cyclization of a particular class of ketenimines bearing N-acylimino units has been studied by ab initio and DFT calculations. In the model compounds the carbonyl carbon atom and the keteniminic nitrogen atom are linked either by a vinylic or an o-phenylene tether. Two cyclization modes have been analyzed: the [2+2] cycloaddition furnishing compounds with an azeto[2,1-b]pyrimidinone moiety and a 6pi-electrocyclic ring closure leading to compounds enclosing a 1,3-oxazine ring. The [2+2] cycloaddition reaction takes place via a two-step process with formation of a zwitterionic intermediate, which has been characterized as a cross-conjugated mesomeric betaine. The 6pi-electrocyclic ring closure occurs via a transition state whose pseudopericyclic character has been established on the basis of its magnetic properties, geometry, and NBO analysis. The 6pi-electrocyclic ring closure is energetically favored over the [2+2] cycloaddition, although the [2+2] cycloadducts are the thermodynamically controlled products. A quantitative kinetic analysis predicts that 1,3-oxazines would be the kinetically controlled products, but they should transform rapidly and totally into the [2+2] cycloadducts at room temperature. In the experimental study, a number of N-acylimino-ketenimines, in which both reactive functions are supported on an o-phenylene scaffold, have been successfully synthesized in three steps starting from 2-azidobenzoyl chloride. These compounds rapidly convert into azeto[2,1-b]quinazolin-8-ones in moderate to good yields as a result of a formal [2+2] cycloaddition.

Fragment and knowledge-based design of selective GSK-3beta inhibitors using virtual screening models.

PubMed

Vadivelan, S; Sinha, Barij Nayan; Tajne, Sunita; Jagarlapudi, Sarma A R P

2009-06-01

Glycogen Synthase Kinase 3beta is one of the important targets in the treatment of type II diabetes and Alzheimer's disease. Currently this target is in pursuit for type II diabetes and a few GSK-3beta inhibitors have been now advanced to Phases I and II of clinical trials. The best validated HypoGen model consists of four pharmacophore features; 1) two hydrogen bond acceptors, 2) one hydrogen bond donor and 3) one hydrophobic. This pharmacophore model correlates well with the docking model, one hydrogen bond acceptor is necessary for the H-bond interaction with VAL135, and second hydrogen bond acceptor is important for the H-bond interactions with ARG141 and the hydrophobic feature may be required for the weak H-bond interactions with ASP133. The comparative model was developed from analogue and structure-based models like Catalyst, Glide SP & XP, Gold Fitness & ChemScore and Ligand Fit using multiple linear regression analysis. A virtual library of 10,000 molecules was generated employing fragment and knowledge-based approach and the comparative model was used to predict the activities of these molecules. The H-bond with ARG141 appears to be unique to GSK-3beta and explains the high GSK-3beta selectivity observed for 1H-Quinazolin-4-ones and Benzo[e][1,3]oxazin-4-ones. This understanding of protein-ligand interactions and molecular recognition increases the rapid development of potent and selective inhibitors, and also helps to eliminate the increase in number of false positives and negatives.

NMR-based platform for fragment-based lead discovery used in screening BRD4-targeted compounds

PubMed Central

Yu, Jun-lan; Chen, Tian-tian; Zhou, Chen; Lian, Fu-lin; Tang, Xu-long; Wen, Yi; Shen, Jing-kang; Xu, Ye-chun; Xiong, Bing; Zhang, Nai-xia

2016-01-01

Aim: Fragment-based lead discovery (FBLD) is a complementary approach in drug research and development. In this study, we established an NMR-based FBLD platform that was used to screen novel scaffolds targeting human bromodomain of BRD4, and investigated the binding interactions between hit compounds and the target protein. Methods: 1D NMR techniques were primarily used to generate the fragment library and to screen compounds. The inhibitory activity of hits on the first bromodomain of BRD4 [BRD4(I)] was examined using fluorescence anisotropy binding assay. 2D NMR and X-ray crystallography were applied to characterize the binding interactions between hit compounds and the target protein. Results: An NMR-based fragment library containing 539 compounds was established, which were clustered into 56 groups (8–10 compounds in each group). Eight hits with new scaffolds were found to inhibit BRD4(I). Four out of the 8 hits (compounds 1, 2, 8 and 9) had IC50 values of 100–260 μmol/L, demonstrating their potential for further BRD4-targeted hit-to-lead optimization. Analysis of the binding interactions revealed that compounds 1 and 2 shared a common quinazolin core structure and bound to BRD4(I) in a non-acetylated lysine mimetic mode. Conclusion: An NMR-based platform for FBLD was established and used in discovery of BRD4-targeted compounds. Four potential hit-to-lead optimization candidates have been found, two of them bound to BRD4(I) in a non-acetylated lysine mimetic mode, being selective BRD4(I) inhibitors. PMID:27238211

The combi-targeting concept: synthesis of stable nitrosoureas designed to inhibit the epidermal growth factor receptor (EGFR).

PubMed

Domarkas, Juozas; Dudouit, Fabienne; Williams, Christopher; Qiyu, Qiu; Banerjee, Ranjita; Brahimi, Fouad; Jean-Claude, Bertrand Jacques

2006-06-15

According to the "combi-targeting" concept, the EGFR tyrosine kinase (TK) inhibitory potency of compounds termed "combi-molecules" is critical for selective growth inhibition of tumor cells with disordered expression of EGFR or its closest family member erbB2. Here we report on the optimization of the EGFR TK inhibitory potency of the combi-molecules of the nitrosourea class by comparison with their aminoquinazoline and ureidoquinazoline precursors. This led to the discovery of a new structural parameter that influences their EGFR TK inhibitory potency, i.e., the torsion angle between the plane of the quinazoline ring and the ureido or the nitrosoureido moiety of the synthesized drugs. Compounds (3'-Cl and Br series) with small angles (0.5-3 degrees ) were generally stronger EGFR TK inhibitors than those with large angles (18-21 degrees ). This was further corroborated by ligand-receptor van der Waals interaction calculations that showed significant binding hindrance imposed by large torsion angles in the narrow ATP cleft of EGFR. Selective antiproliferative studies in a pair of mouse fibroblast NIH3T3 cells, one of which NIH3T3/neu being transfected with the erbB2 oncogene, showed that IC(50) values for inhibition of EGFR TK could be good predictors of their selective potency against the serum-stimulated growth of the erbB2-tranfected cell line (Pearson r = 0.8). On the basis of stability (t(1/2)), EGFR TK inhibitory potency (IC(50)), and selective erbB2 targeting, compound 23, a stable nitrosourea, was considered to have the structural requirements for further development.

The centroidal algorithm in molecular similarity and diversity calculations on confidential datasets.

PubMed

Trepalin, Sergey; Osadchiy, Nikolay

2005-01-01

Chemical structure provides exhaustive description of a compound, but it is often proprietary and thus an impediment in the exchange of information. For example, structure disclosure is often needed for the selection of most similar or dissimilar compounds. Authors propose a centroidal algorithm based on structural fragments (screens) that can be efficiently used for the similarity and diversity selections without disclosing structures from the reference set. For an increased security purposes, authors recommend that such set contains at least some tens of structures. Analysis of reverse engineering feasibility showed that the problem difficulty grows with decrease of the screen's radius. The algorithm is illustrated with concrete calculations on known steroidal, quinoline, and quinazoline drugs. We also investigate a problem of scaffold identification in combinatorial library dataset. The results show that relatively small screens of radius equal to 2 bond lengths perform well in the similarity sorting, while radius 4 screens yield better results in diversity sorting. The software implementation of the algorithm taking SDF file with a reference set generates screens of various radii which are subsequently used for the similarity and diversity sorting of external SDFs. Since the reverse engineering of the reference set molecules from their screens has the same difficulty as the RSA asymmetric encryption algorithm, generated screens can be stored openly without further encryption. This approach ensures an end user transfers only a set of structural fragments and no other data. Like other algorithms of encryption, the centroid algorithm cannot give 100% guarantee of protecting a chemical structure from dataset, but probability of initial structure identification is very small-order of 10(-40) in typical cases.

The centroidal algorithm in molecular similarity and diversity calculations on confidential datasets

NASA Astrophysics Data System (ADS)

Trepalin, Sergey; Osadchiy, Nikolay

2005-09-01

Chemical structure provides exhaustive description of a compound, but it is often proprietary and thus an impediment in the exchange of information. For example, structure disclosure is often needed for the selection of most similar or dissimilar compounds. Authors propose a centroidal algorithm based on structural fragments (screens) that can be efficiently used for the similarity and diversity selections without disclosing structures from the reference set. For an increased security purposes, authors recommend that such set contains at least some tens of structures. Analysis of reverse engineering feasibility showed that the problem difficulty grows with decrease of the screen's radius. The algorithm is illustrated with concrete calculations on known steroidal, quinoline, and quinazoline drugs. We also investigate a problem of scaffold identification in combinatorial library dataset. The results show that relatively small screens of radius equal to 2 bond lengths perform well in the similarity sorting, while radius 4 screens yield better results in diversity sorting. The software implementation of the algorithm taking SDF file with a reference set generates screens of various radii which are subsequently used for the similarity and diversity sorting of external SDFs. Since the reverse engineering of the reference set molecules from their screens has the same difficulty as the RSA asymmetric encryption algorithm, generated screens can be stored openly without further encryption. This approach ensures an end user transfers only a set of structural fragments and no other data. Like other algorithms of encryption, the centroid algorithm cannot give 100% guarantee of protecting a chemical structure from dataset, but probability of initial structure identification is very small-order of 10-40 in typical cases.

The DcpS inhibitor RG3039 improves survival, function and motor unit pathologies in two SMA mouse models

PubMed Central

Gogliotti, Rocky G.; Cardona, Herminio; Singh, Jasbir; Bail, Sophie; Emery, Carina; Kuntz, Nancy; Jorgensen, Michael; Durens, Madel; Xia, Bing; Barlow, Courtenay; Heier, Christopher R.; Plasterer, Heather L.; Jacques, Vincent; Kiledjian, Megerditch; Jarecki, Jill; Rusche, James; DiDonato, Christine J.

2013-01-01

Spinal muscular atrophy (SMA) is caused by insufficient levels of the survival motor neuron (SMN) protein due to the functional loss of the SMN1 gene and the inability of its paralog, SMN2, to fully compensate due to reduced exon 7 splicing efficiency. Since SMA patients have at least one copy of SMN2, drug discovery campaigns have sought to identify SMN2 inducers. C5-substituted quinazolines increase SMN2 promoter activity in cell-based assays and a derivative, RG3039, has progressed to clinical testing. It is orally bioavailable, brain-penetrant and has been shown to be an inhibitor of the mRNA decapping enzyme, DcpS. Our pharmacological characterization of RG3039, reported here, demonstrates that RG3039 can extend survival and improve function in two SMA mouse models of varying disease severity (Taiwanese 5058 Hemi and 2B/− SMA mice), and positively impacts neuromuscular pathologies. In 2B/− SMA mice, RG3039 provided a >600% survival benefit (median 18 days to >112 days) when dosing began at P4, highlighting the importance of early intervention. We determined the minimum effective dose and the associated pharmacokinetic (PK) and exposure relationship of RG3039 and DcpS inhibition ex vivo. These data support the long PK half-life with extended pharmacodynamic outcome of RG3039 in 2B/− SMA mice. In motor neurons, RG3039 significantly increased both the average number of cells with gems and average number of gems per cell, which is used as an indirect measure of SMN levels. These studies contribute to dose selection and exposure estimates for the first studies with RG3039 in human subjects. PMID:23736298

Therapeutic and cosmetic applications of Evodiamine and its derivatives--A patent review.

PubMed

Gavaraskar, Kirti; Dhulap, Sivakami; Hirwani, R R

2015-10-01

Evodiamine, ((+)-(S)-8,13,13b,14-tetrahydro-14-methylindolo[2',3':3,4]pyrido[2,1-b]quinazolin-5(7H)-one) indoloquinazoline alkaloid, is the major component isolated from the fruits of Evodia rutaecarpa, family Rutaceae. Broad spectrum of pharmacological activities of Evodiamine suggests its imperative role in treating a variety of diseases influencing the function of diverse targets. A comprehensive search was carried out to collect patent information regarding Evodiamine and its derivatives using different patent databases covering priority years to till date. The patents claiming therapeutic as well as cosmetic applications of Evodiamine and its derivatives were analyzed in detail and were classified technically based on the its application such as treatment of metabolic disorders, cancer, neurological disorders, and cardiovascular disorders, etc. The analysis revealed that the use and the mode of actions of Evodiamine and its derivatives in weight management treatments are currently well established. For example the fat reducing property of this alkaloid is primarily due to its mode of actions such as prevention of muscle protein catabolism, enhancement of thermogenesis and lipid oxidation. Apart from its use for treating obesity, Evodiamine and its derivatives are also experimentally explored for their anti-cancer, anti-diabetic and anti-inflammatory properties. The possible mechanisms related to its anti-cancer activity as illustrated by different experimental studies include its potential action as modulator of specific receptors such as topoisomerase I, NF-kappa B and B-cell lymphoma 2 (Bcl2). The analysis hence highlights that, clinical studies pertaining to the anti-cancer, anti-diabetes as well as anti-inflammatory activities of the Evodiamine and its derivatives would possess important market potential for the development of Evodiamine based therapeutics. Copyright © 2015 Elsevier B.V. All rights reserved.

Mechanisms of acquired resistance to the quinazoline thymidylate synthase inhibitor ZD1694 (Tomudex) in one mouse and three human cell lines.

PubMed Central

Jackman, A. L.; Kelland, L. R.; Kimbell, R.; Brown, M.; Gibson, W.; Aherne, G. W.; Hardcastle, A.; Boyle, F. T.

1995-01-01

Four cell lines, the mouse L1210 leukaemia, the human W1L2 lymphoblastoid and two human ovarian (CH1 and 41M) cell lines, were made resistant to ZD1694 (Tomudex) by continual exposure to incremental doses of the drug. A 500-fold increase in thymidylate synthase (TS) activity is the primary mechanism of resistance to ZD1694 in the W1L2:RD1694 cell line, which is consequently highly cross-resistant to other folate-based TS inhibitors, including BW1843U89, LY231514 and AG337, but sensitive to antifolates with other enzyme targets. The CH1:RD1694 cell line is 14-fold resistant to ZD1694, largely accounted for by the 4.2-fold increase in TS activity. Cross-resistance was observed to other TS inhibitors, including 5-fluorodeoxyuridine (FdUrd). 41M:RD1694 cells, when exposed to 0.1 microM [3H]ZD1694, accumulated approximately 20-fold less 3H-labelled material over 24 h than the parental line. Data are consistent with this being the result of impaired transport of the drug via the reduced folate/methotrexate carrier. Resistance was therefore observed to methotrexate but not to CB3717, a compound known to use this transport mechanism poorly. The mouse L1210:RD1694 cell line does not accumulate ZD1694 or Methotrexate (MTX) polyglutamates. Folylpolyglutamate synthetase substrate activity (using ZD1694 as the substrate) was decreased to approximately 13% of that observed in the parental line. Cross-resistance was found to those compounds known to be active through polyglutamation. PMID:7537518

Additive effect of multiple pharmacological chaperones on maturation of CFTR processing mutants

PubMed Central

Wang, Ying; Loo, Tip W.; Bartlett, M. Claire; Clarke, David M.

2007-01-01

The most common cause of CF (cystic fibrosis) is the deletion of Phe508 (ΔF508) in the CFTR [CF TM (transmembrane) conductance regulator] chloride channel. One major problem with ΔF508 CFTR is that the protein is defective in folding so that little mature protein is delivered to the cell surface. Expression of ΔF508 CFTR in the presence of small molecules known as correctors or pharmacological chaperones can increase the level of mature protein. Unfortunately, the efficiency of corrector-induced maturation of ΔF508 CFTR is probably too low to have therapeutic value and approaches are needed to increase maturation efficiency. We postulated that expression of ΔF508 CFTR in the presence of multiple correctors that bound to different sites may have an additive effect on maturation. In support of this mechanism, we found that expression of P-glycoprotein (CFTR's sister protein) processing mutants in the presence of two compounds that bind to different sites (rhodamine B and Hoechst 33342) had an additive effect on maturation. Therefore we tested whether expression of ΔF508 CFTR in the presence of combinations of three different classes of corrector molecules would increase its maturation efficiency. It was found that the combination of the quinazoline VRT-325 together with the thiazole corr-2b or bisaminomethylbithiazole corr-4a doubled the steady-state maturation efficiency of ΔF508 CFTR (approx. 40% of total CFTR was mature protein) compared with expression in the presence of a single compound. The additive effect of the correctors on ΔF508 CFTR maturation suggests that they directly interact at different sites of the protein. PMID:17535157

Histone lysine methyltransferase structure activity relationships that allow for segregation of G9a inhibition and anti-Plasmodium activity† †The authors declare no competing interests. ‡ ‡Electronic supplementary information (ESI) available: Supplementary Tables ST1–ST5, experimental data for the representative diaminoquinazoline analogues, 2D NMRs of 85 and 111a and X-ray structure of 111a (Fig. SF1). The coordinates for 111a have been deposited with CCDC 1503377. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c7md00052a

PubMed Central

Sundriyal, Sandeep; Chen, Patty B.; Lubin, Alexandra S.; Lueg, Gregor A.; Li, Fengling; White, Andrew J. P.; Malmquist, Nicholas A.; Vedadi, Masoud; Scherf, Artur

2017-01-01

Plasmodium falciparum HKMTs (PfHKMTs) play a key role in controlling Plasmodium gene expression and represent exciting new anti-malarial epigenetic targets. Using an inhibitor series derived from the diaminoquinazoline HKMT inhibitory chemotype, we have previously identified compounds with highly promising antimalarial activity, including irreversible asexual cycle blood stage-independent cytotoxic activity at nM concentrations, oral efficacy in in vivo models of disease, and the unprecedented ability to reactivate dormant liver stage parasites (hypnozoites). However, future development of this series will need to address host versus parasite selectivity, where inhibitory activity against human G9a is removed from the lead compounds, while maintaining potent anti-Plasmodium activity. Herein, we report an extensive study of the SAR of this series against both G9a and P. falciparum. We have identified key SAR features which demonstrate that high parasite vs. G9a selectivity can be achieved by selecting appropriate substituents at position 2, 4 and 7 of the quinazoline ring. We have also, in turn, discovered that potent G9a inhibitors can be identified by employing a 6-carbon ‘Nle mimic’ at position 7. Together, this data suggests that while broadly similar, the G9a and potential PfHKMT target(s) binding pockets and/or binding modes of the diaminoquinazoline analogues exhibit clear and exploitable differences. Based on this, we believe this scaffold to have clear potential for development into a novel anti-malarial therapeutic. PMID:29308121

Tandem 1,5-hydride shift/1,5-S,N-cyclization with ethylene extrusion of 1,3-oxathiolane-substituted ketenimines and carbodiimides. An experimental and computational study.

PubMed

Alajarin, Mateo; Bonillo, Baltasar; Sanchez-Andrada, Pilar; Vidal, Angel

2010-06-04

Under thermal activation in solution, N-[2-(1,3-oxathiolan-2-yl)]phenyl ketenimines and carbodiimides were converted into 2,1-benzisothiazol-3-ones bearing a pendant N-styryl or imidoyl fragment, respectively. These processes should occur with the concomitant formation of ethylene as result of the fragmentation of the 1,3-oxathiolane ring. The conversions of ketenimines took place under softer thermal conditions, toluene 110 degrees C, than those of carbodiimides, o-xylene 160 degrees C. A computational DFT study unveiled the mechanistic course of these transformations, rare tandem processes consisting of an initial 1,5-hydride shift of the acetalic hydrogen atom to the central carbon atom of the heterocumulene function leading to the respective o-azaxylylene. This transient intermediate then converts, in a single step, into ethylene and the experimentally isolated benzisothiazolone. This latter stage of the mechanism is rather peculiar, combining a 1,5-cyclization by S-N bond formation, aromaticity recovery at the benzene nucleus, and the fragmentation of the oxathiolane framework originating a new carbonyl group. It can be related with a vinylogous retro-ene reaction and shows pseudopericyclic characteristics. The computations also revealed that the alternative 6pi electrocyclization of the transient o-azaxylylenes cannot compete, on kinetic and thermodynamic grounds, with the experimentally observed reaction channel. The two alternative reaction paths of a number of ketenimines and carbodiimides were computationally scrutinized, the results being in accord with the experimental outcomes. In addition, sulfur extrusion from the benzisothiazolones by the action of triphenylphosphine under two different reaction conditions led to three different types of heterocyclic products, 4(3H)-quinolones, quinolino[2,1-b]quinazolin-5,12-diones, and dibenzo[b,f][1,5]diazocin-6,12-diones, whose formation is explained by the initial formation of an intermediate imidoylketene. This reactive species could be trapped by a nucleophilic solvent, ethanol.

Rapid, sensitive, and validated UPLC/Q-TOF-MS method for quantitative determination of vasicine in Adhatoda vasica and its in vitro culture

PubMed Central

Madhukar, Garg; Tamboli, Ennus Tajuddin; Rabea, Parveen; Ansari, S. H.; Abdin, M. Z.; Sayeed, Ahmad

2014-01-01

Background: Adhatoda vasica a perennial herb has been used in Ayurvedic and Unani system of medicines since last 2000 years and has been employed for the treatment of respiratory tract ailments. Objective: To develop and validate new, rapid, and highly sensitive high throughput ultra-performance liquid chromatography/quadrupole-time-of-flight mass-spectrometry (UPLC/Q-TOF-MS) method for the quantitative estimation of vasicine in the leaves and to establish in vitro cultures of Adhatoda vasica for production of vasicine. Materials and Methods: The chromatographic separation was achieved on a Waters ACQUITY UPLC™ BEH C8 (100.0 × 2.1 mm; 1.7 μm) column packing using isocratic mobile phase consisting of acetonitrile: 20 mM ammonium acetate (90:10; v/v) in a multiple reactions monitoring mode using the transitions m/z 189.09 → 171.08 for vasicine. Results: The vasicine was eluted at 2.58 ± 0.05 min and established a dynamic range of linearity over the concentration range of 1-1000 ng/ml (r2 = 0.999 ± 0.0005). The lower limit of detection and quantification was 0.68 and 1.0 ng/ml, respectively. There was no significant difference observed in the content of vasicine (0.92-1.04%w/w) among the eleven samples collected from different locations of India. The in vitro cultures developed showed that addition of extra 28 mM KNO3 and 100 mM NaCl in MS medium supplemented with 2,4-dichlorophenoxyacetic acid (2,4-D) + benzyladenine (BA) + indole acetic acid (IAA) (1 ppm each) produces faster biomass and higher amount of quinazoline alkaloids. Conclusion: Rapid, efficient, and sensitive UPLC/Q-TOF-MS method was developed for the estimation of vasicine and an efficient protocol for development of in vitro cultures was proposed, which can be used at large scale for industrial production of vasicine using bioreactors. PMID:24914304

Analysis of violet-excited fluorochromes by flow cytometry using a violet laser diode.

PubMed

Telford, William G; Hawley, Teresa S; Hawley, Robert G

2003-07-01

Low power violet laser diodes (VLDs) have been evaluated as potential replacements for water-cooled argon-ion and krypton-ion ultraviolet and violet lasers for DNA content analysis using the Hoechst dyes and 4,6-diamidino-2-phenylindole (Shapiro HMN, Perlmutter NG: Cytometry 44:133-136, 2001). In this study, we used a VLD to excite a variety of violet-excited fluorescent molecules important in biomedical analysis, including the fluorochromes Cascade Blue and Pacific Blue, the expressible fluorescent protein cyan fluorescent protein (CFP), and the fluorogenic alkaline phosphatase (AP) substrate 2-(5'-chloro-2'-phosphoryloxyphenyl)-6-chloro-4-(3H)-quinazoline (ELF-97; for endogenous AP detection and cell surface labeling with AP-conjugated antibodies). Comparisons were made between VLD excitation and a krypton-ion laser emitting at 407 nm (both at higher power levels and with the beam attenuated at levels approximating the VLD) on the same FACSVantage SE stream-in-air flow cytometer. We evaluated a Power Technology 408-nm VLD (30 mW) equipped with circularization optics (18 mW maximum output, set to 15 mW) and a Coherent I-302C krypton-ion laser emitting at power levels ranging from 15 to 75 mW. Cascade Blue, Pacific Blue, and CFP showed comparable signal-to-noise ratios and levels of sensitivity with VLD excitation versus the krypton-ion laser at high and VLD-matched power outputs. Multicolor fluorescent protein analysis with 488-nm excitation of green fluorescent protein and DsRed and VLD excitation of CFP was therefore feasible and was demonstrated. Similar levels of excitation efficiency between krypton-ion and VLD sources also were observed for ELF-97 detection. These evaluations confirmed that VLDs may be cost- and maintenance-effective replacements for water-cooled gas lasers for applications requiring violet excitation in addition to DNA binding dyes. Published 2003 Wiley-Liss, Inc.

A novel DYRK1A (dual specificity tyrosine phosphorylation-regulated kinase 1A) inhibitor for the treatment of Alzheimer's disease: effect on Tau and amyloid pathologies in vitro.

PubMed

Coutadeur, Séverine; Benyamine, Hélène; Delalonde, Laurence; de Oliveira, Catherine; Leblond, Bertrand; Foucourt, Alicia; Besson, Thierry; Casagrande, Anne-Sophie; Taverne, Thierry; Girard, Angélique; Pando, Matthew P; Désiré, Laurent

2015-05-01

The dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) gene is located within the Down Syndrome (DS) critical region on chromosome 21 and is implicated in the generation of Tau and amyloid pathologies that are associated with the early onset Alzheimer's Disease (AD) observed in DS. DYRK1A is also found associated with neurofibrillary tangles in sporadic AD and phosphorylates key AD players (Tau, amyloid precursor, protein, etc). Thus, DYRK1A may be an important therapeutic target to modify the course of Tau and amyloid beta (Aβ) pathologies. Here, we describe EHT 5372 (methyl 9-(2,4-dichlorophenylamino) thiazolo[5,4-f]quinazoline-2-carbimidate), a novel, highly potent (IC50 = 0.22 nM) DYRK1A inhibitor with a high degree of selectivity over 339 kinases. Models in which inhibition of DYRK1A by siRNA reduced and DYRK1A over-expression induced Tau phosphorylation or Aβ production were used. EHT 5372 inhibits DYRK1A-induced Tau phosphorylation at multiple AD-relevant sites in biochemical and cellular assays. EHT 5372 also normalizes both Aβ-induced Tau phosphorylation and DYRK1A-stimulated Aβ production. DYRK1A is thus as a key element of Aβ-mediated Tau hyperphosphorylation, which links Tau and amyloid pathologies. EHT 5372 and other compounds in its class warrant in vivo investigation as a novel, high-potential therapy for AD and other Tau opathies. Inhibition of the dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) is a new high-potential therapeutic approach for Alzheimer disease. Here we describe EHT 5372, a novel potent and selective DYRK1A inhibitor. EHT 5372 inhibits DYRK1A-induced Tau phosphorylation, Aβ production and Aβ effects on phospho-Tau, including Tau aggregation. © 2014 International Society for Neurochemistry.

Evaluation of Three Small Molecular Drugs for Targeted Therapy to Treat Nonsmall Cell Lung Cancer

PubMed Central

Ni, Jun; Zhang, Li

2016-01-01

Objective: To guide the optimal selection among first-generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) in clinical practice. This review attempted to provide a thorough comparison among three first-generation EGFR-TKIs, namely icotinib, erlotinib, and gefitinib, with regard to their molecular structure, pharmacokinetic parameters, clinical data, adverse reactions, and contraindications. Data Sources: An electronic literature search of the PubMed database and Google Scholar for all the available articles regarding gefitinib, icotinib, and erlotinib in the English language from January 2005 to December 2014 was used. Study Selection: The search terms or keywords included but not limited to “lung cancer”, “nonsmall cell lung cancer (NSCLC)”, “epidemiology”, “EGFR”, “TKIs”, and “optimal selection”. Results: As suggested by this review, even though the three first-generation EGFR-TKIs share the quinazoline structure, erlotinib had the strongest apoptosis induction activity because of its use of a different side-chain. The pharmacokinetic parameters indicated that both erlotinib and icotinib are affected by food. The therapeutic window of erlotinib is narrow, and the recommended dosage is close to the maximum tolerable dosage. Icotinib enjoys a wider therapeutic window, and its concentration in the blood is within a safe dosage range even if it is administered with food. Based on multiple large-scale clinical trials, erlotinib is universally applied as the first-line treatment. In marked contrast, icotinib is available only in China as the second- or third-line therapeutic approach for treating advanced lung cancer. In addition, it exhibits a similar efficacy but better safety profile than gefitinib. Conclusions: Although there is a paucity of literature regarding whether icotinib is superior to erlotinib, its superior toxicity profile, noninferior efficacy, and lower cost indicate that it is a better alternative for Chinese patients living with advanced NSCLC. PMID:26831237

Effect of the CYP2C19 genotype on the pharmacokinetics of icotinib in healthy male volunteers.

PubMed

Ruan, Can-Jun; Liu, Dong-Yang; Jiang, Ji; Hu, Pei

2012-12-01

Icotinib hydrochloride {4-[(3-ethynylphenyl)amino]-6,7-benzo-12-crown-4-quinazoline hydrochloride}, a novel epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), was designed for the treatment of non-small cell lung cancer (NSCLC). In the present study, we investigated the influence of the CYP2C19*2 and CYP2C19*3 alleles on the pharmacokinetics of icotinib in healthy Chinese volunteers. In a single-dose pharmacokinetic study, 12 healthy Chinese volunteers received an oral dose of 600 mg of icotinib. Plasma was sampled for up to 72 h post-dose, followed by quantification of icotinib by liquid chromatography-mass spectrometry/mass spectrometry (LC-MS-MS). Five subjects genotyped as homozygous extensive metabolizers (CYP2C19*1/*1), 6 subjects genotyped as heterozygous extensive metabolizers (CYP2C19*1/*2 or CYP2C19*1/*3), and 1 subject genotyped as a poor metabolizer (CYP2C19*2/*3) and was withdrawn from the research because of urticaria. The mean icotinib AUC(0-∞) and C(max) (14.56 ±5.31 h mg/L and 2.32 ± 0.49 μg/mL) in homozygous EMs was 1.56 and 1.41-fold lower than that in heterozygous EMs (22.7 ± 6.11 and 3.28 ± 0.48, P = 0.046 and 0.047). The mean CL/F (44.18 ± 12.17 L/h) in homozygous EMs was 1.55-fold higher than that in heterozygous EMs (28.42 ± 9.23 L/h, P = 0.013). The data showed that the pharmacokinetics of icotinib differ significantly between homozygous EMs and heterozygous EMs in CYP2C19.

Toxicity Assessment of the Xanthid Crab Demania cultripes from Cebu Island, Philippines

PubMed Central

Asakawa, Manabu; Gomez-Delan, Gloria; Tsuruda, Shintaro; Shimomura, Michitaka; Shida, Yasuo; Taniyama, Shigeto; Barte-Quilantang, Mercy; Shindo, Jo

2010-01-01

Several cases of poisoning resulting in human fatalities and stemming from the ingestion of coral reef crabs have been reported from the Indo-Pacific region. We assessed the toxicity of the unidentified xanthid crab collected from the Camotes Sea off the eastern coast of Cebu Island, central Visayas region of Philippines from the food hygienic point of view. All seven specimens, which were identified with Demania cultripes, collected in 2006 were toxic to mice irrespective of the season of collection and induced paralytic symptoms typical of tetrodotoxin (TTX) and paralytic shellfish poison (PSP). The activity was expressed in mouse unit (MU) being defined as the amount of TTX to kill a 20 g ddY male mice in 30 min after i.p. injection. Toxicity scores for viscera and appendages of specimens were 18.2 ± 16.0 (mean ± S.D.) and 4.4 ± 2.6 MU/g, respectively. The highest individual toxicity scores observed for viscera and appendages were 52.1 and 7.7 MU/g, respectively. The frequency of toxic samples was 100%. Toxin profiles as determined by high-performance liquid chromatography-fluorescent detection analysis (HPLC-FLD) revealed that TTX was the main toxic principle accounting for about 90% of the total toxicity along with 4-epi TTX and 4,9-anhydroTTX. Furthermore, gas chromatography-mass spectrometry (GC-MS) analysis revealed mass fragment ion peaks at m/z 376, 392 and 407, which were characteristic of the quinazoline skeleton (C9-base) specific to TTX. In addition, only a small amount of PSP containing gonyautoxins1–4 and hydroxysaxitoxin was detected. To our knowledge, this is the first report presenting evidence of occurrence of TTX and PSP in the xanthid crab D. cultripes inhabiting waters surrounding Cebu Island. From food hygienic point of view, people in coastal areas should be warned of the potential hazard of this crab in order to prevent its intentional or accidental consumption. PMID:21209702

Reaction of diazepam and related benzodiazepines with chlorine. Kinetics, transformation products and in-silico toxicological assessment.

PubMed

Carpinteiro, Inmaculada; Rodil, Rosario; Quintana, José Benito; Cela, Rafael

2017-09-01

In this work, the reaction of four benzodiazepines (diazepam, oxazepam, nordazepam and temazepam) during water chlorination was studied by means of liquid chromatography-quadrupole-time of flight-mass spectrometry (LC-QTOF-MS). For those compounds that showed a significant degradation, i.e. diazepam, oxazepam and nordazepam, parameters affecting to the reaction kinetics (pH, chlorine and bromide level) were studied in detail and transformation products were tentatively identified. The oxidation reactions followed pseudofirst-order kinetics with rate constants in the range of 1.8-42.5 M -1  s -1 , 0.13-1.16 M -1  s -1 and 0.04-20.4 M -1  s -1 corresponding to half-life values in the range of 1.9-146 min, 1.8-87 h and 2.5-637 h for oxazepam, nordazepam and diazepam, respectively, depending of the levels of studied parameters. Chlorine and pH affected significantly the reaction kinetics, where an increase of the pH resulted into a decrease of the reaction rate, whereas higher chlorine dosages led to faster kinetics, as expected in this case. The transformation of the studied benzodiazepines occurs mainly at the 1,4-diazepine 7-membered-ring, resulting in ring opening to form benzophenone derivatives or the formation of a 6-membered pyrimidine ring, leading to quinazoline derivatives. The formation of these by-products was also tested in real surface water samples observing kinetics of oxazepam degradation slower in river than in creek water, while the degradation of the two other benzodiazepines occurred only in the simpler sample (creek water). Finally, the acute and chronical toxicity and mutagenicity of precursors and transformation products were estimated using quantitative structure-activity relationship (QSAR) software tools: Ecological Structure Activity Relationships (ECOSAR) and Toxicity Estimation Software Tool (TEST), finding that some transformation products could be more toxic/mutagenic than the precursor drug, but additional test would be needed to confirm this fact. Copyright © 2017 Elsevier Ltd. All rights reserved.

Methanol adducts leading to the identification of a reactive aldehyde metabolite of CPAQOP in human liver microsomes by ultra-high-performance liquid chromatography/mass spectrometry.

PubMed

Martin, Scott; Lenz, Eva M; Smith, Robin; Temesi, David G; Orton, Alexandra L; Clench, Malcolm R

2017-01-15

The incubation of CPAQOP (1-[(2R)-2-[[4-[3-chloro-4-(2-pyridyloxy)anilino]quinazolin-5-yl]oxymethyl]-1-piperidyl]-2-hydroxy) with human liver microsomes generated several metabolites that highlighted the hydroxyacetamide side chain was a major site of metabolism for the molecule. The metabolites were derived predominantly from oxidative biotransformations; however, two unexpected products were detected by liquid chromatography/ultraviolet/mass spectrometry (LC/UV/MS) and identified as methanol adducts. This observation prompted further LC/MS investigations into their formation. Three separate incubations of CPAQOP were conducted in human liver microsomes; Naïve, fortified with methoxyamine and fortified with glutathione. Separation was achieved via ultra-high-performance liquid chromatography with either methanol or acetonitrile gradients containing formic acid. MS analysis was conducted by electrospray ionisation LTQ Orbitrap mass spectrometry acquiring accurate mass full scan, data-dependent MS 2 and all ion fragmentation. No methanol adducts were detected by MS when acetonitrile was used in the mobile phase instead of methanol, verifying that a metabolite was reacting with methanol on column. Although this reactive metabolite could not be isolated or structurally characterised by LC/MS directly, product ion spectra of the methanol adducts confirmed addition of methanol on the hydroxyacetamide side chain. Additional experiments using methoxyamine showed the disappearance of the two methanol adducts and appearance of a methoxyamine adduct, confirming the presence of an aldhyde. Product ion spectra of the methoxyamine adduct confirmed addition of methoxyamine to the hydroxyacetamide side chain. The proposed bioactivation of CPAQOP occurred via the reactive aldehyde intermediate, which readily reacted with methanol in the mobile phase to form a pair of isomeric hemiacetal methanol adducts. In acidified methanol the equilibrium favoured the methanol adduct and in acidified acetonitrile it favoured the hydrate; therefore, the reactive aldehyde metabolite was not detected and could not be structurally characterised directly. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Pinpoint chemical modification of Asp160 in the 49 kDa subunit of bovine mitochondrial complex I via a combination of ligand-directed tosyl chemistry and click chemistry.

PubMed

Masuya, Takahiro; Murai, Masatoshi; Morisaka, Hironobu; Miyoshi, Hideto

2014-12-16

Through a ligand-directed tosyl (LDT) chemistry strategy using the synthetic acetogenin ligand AL1, we succeeded in the pinpoint alkynylation (-C≡CH) of Asp160 in the 49 kDa subunit of bovine complex I, which may be located in the inner part of the putative quinone binding cavity of the enzyme [Masuya, T., et al. (2014) Biochemistry, 53, 2307-2317]. This study provided a promising technique for diverse chemical modifications of complex I. To further improve this technique for its adaptation to intact complex I, we here synthesized the new acetogenin ligand AL2, possessing an azido (-N₃) group in place of the terminal alkyne in AL1, and attempted the pinpoint azidation of complex I in bovine heart submitochondrial particles. Careful proteomic analyses revealed that, just as in the case of AL1, azidation occurred at 49 kDa Asp160 with a reaction yield of ∼50%, verifying the high site specificity of our LDT chemistry using acetogenin ligands. This finding prompted us to speculate that a reactivity of the azido group incorporated into Asp160 (Asp160-N₃) against externally added chemicals can be employed to characterize the structural features of the quinone/inhibitor binding cavity. Consequently, we used a ring-strained cycloalkyne possessing a rhodamine fluorophore (TAMRA-DIBO), which can covalently attach to an azido group via so-called click chemistry without Cu¹⁺ catalysis, as the reaction partner of Asp160-N₃. We found that bulky TAMRA-DIBO is capable of reacting directly with Asp160-N₃ in intact complex I. Unexpectedly, the presence of an excess amount of short-chain ubiquinones as well as some strong inhibitors (e.g., quinazoline and fenpyroximate) did not interfere with the reaction between TAMRA-DIBO and Asp160-N₃; nevertheless, bullatacin, a member of the natural acetogenins, markedly interfered with this reaction. Taking the marked bulkiness of TAMRA-DIBO into consideration, it appears to be difficult to reconcile these results with the proposal that only a narrow entry point accessing to the quinone/inhibitor binding cavity exists in complex I [Baradaran, R., et al. (2013) Nature, 494, 443-448]; rather, they suggest that there may be another access path for TAMRA-DIBO to the cavity.

Pharmacokinetic study of single- and multiple-dosing with metolazone tablets in healthy Chinese population.

PubMed

Li, Xueqing; Wang, Rutao; Liu, Yang; Liu, Yun; Zheng, Heng; Feng, Yabo; Zhao, Na; Geng, Hongbin; Zhang, Wanzhi; Wen, Aidong

2017-11-16

Metolazone is a diuretic, saluretic and antihypertensive chemical compound from the quinazoline category that possesses medicinal features similar to those of other thiazide diuretic drugs. However, the pharmacokinetics of metolazone in the Chinese population has rarely been studied. This study aimed to examine the pharmacokinetic characteristics, safety characteristic, and tolerability of metolazone in healthy Chinese subjects after single and multiple doses taken orally as well as the effects that food and gender have on oral metolazone pharmacokinetic parameters. An open-label, randomized, and single- and multiple-dosing investigation was performed in healthy Chinese subjects. The investigation included 3 study groups: the 0.5 mg, 1 mg and 2 mg dose groups were the single-dose study groups in the first stage. Eligible volunteers were randomly and orally administered a single 0.5 mg, 1 mg, or 2 mg metolazone tablet. The 0.5 mg dose group was also part of the multiple-dose study group, and the 1 mg dose group was the food-effect study group in the second stage. Human plasma samples were gathered pre-dosing and up to 48 h after dosing. The human plasma sample concentration of metolazone was quantified using a validated liquid chromatography tandem mass spectrometry method. Pharmacokinetic data were calculated by a noncompartmental analysis method using WinNonlin version 6.4. Tolerability was evaluated based on adverse events, medical examination, 12-lead ECG, and other clinical laboratory exams. Thirty eligible subjects (15 men and 15 women) were registered in our investigation and completed all of the study stages. The AUC and C max showed dose proportionality after a single dose based on the linear-regression analysis. A comparison of the pharmacokinetic data revealed that the differences between the male and female groups were not statistically significant. The t max of metolazone was increased by approximately 100% in the fed condition. Metolazone was well tolerated at the tested dose, and no adverse effects were observed. Single dosing with 0.5 mg, 1 mg, or 2 mg metolazone yielded linear plasma pharmacokinetic properties in healthy Chinese subjects. Multiple oral doses of metolazone did not display significantly different distributions or elimination characteristics from those observed for a single dose. Gender factors did not appear to influence the pharmacokinetic parameter variation of metolazone. The t max of metolazone increased in the fed condition. Metolazone was well tolerated at the tested dose in this study. This investigation is retrospectively registered at chictr.org.cn (ChiCTR-IIR-17012929, October 09 2017).

The Oxime Portmanteau Motif: Released Heteroradicals Undergo Incisive EPR Interrogation and Deliver Diverse Heterocycles

PubMed Central

2014-01-01

Conspectus Selective syntheses are now available for compounds of many classes, based on C-centered radicals, exploiting a diverse range of mechanisms. The prospect for chemistry based around N- and O-centered radicals is probably more favorable because of the importance of heterocycles as biologically active materials. Heteroradical chemistry is still comparatively underdeveloped due to the need for safe and easy ways of generating them. Oxime esters appeared promising candidates to meet this need because literature reports and our EPR spectroscopic examinations showed they readily dissociated on photolysis with production of a pair of N- and O-centered radicals. It soon became apparent that a whole suite of benign oxime-containing molecules could be pressed into service. The bimodality of the oxime motif meant that by suitable choice of functionality the reactions could be directed to yield selectively products from either the N-centered radicals or from the O-centered radicals. We found that on one hand photolyses of acetophenone oxime esters of carboxylic acids yielded alicyclics. On the other hand, aromatic and heteroaromatic acyl oximes (as well as dioxime oxalates) afforded good yields of phenanthridines and related heterocycles. Easily prepared oxime oxalate amides released carbamoyl radicals, and pleasingly, β-lactams were thereby obtained. Oxime carbonates and oxime carbamates, available via our novel 1,1'-carbonyldiimidazole (CDI)-based preparations, were accessible alternatives for iminyl radicals and hence for phenanthridine preparations. In their second modes, these compounds proved their value as precursors for exotic alkoxycarbonyloxyl and carbamoyloxyl radicals. Microwave-assistance was shown to be a particularly convenient procedure with O-phenyl oxime ethers. The iminyl radicals generated from such precursors with alkene, alkyne, and aromatic acceptor substituents furnished pyrrole, quinoline, phenanthridine, benzonaphthiridine, indolopyridine, and other systems. Microwave irradiations with 2-(aminoaryl)alkanone O-phenyl oximes enabled either dihydroquinazolines or quinazolines to be obtained in very good yields. The fine quality of the EPR spectra, acquired during photolyses of all the O-carbonyl oxime types, marked this as an important complement to existing ways of obtaining such spectra in solution. Quantifications enabled SARs to be obtained for key reaction types of N- and O-centered radicals, thus putting mechanistic chemistry in this area on a much firmer footing. Surprises included the inverse gem-dimethyl effect in 5-exo-cyclizations of iminyls and the interplay of spiro- with ortho-cyclization onto aromatics. Insights into unusual 4-exo-cyclizations of carbamoyl radicals showed the process to be more viable than pent-4-enyl 4-exo-ring closure. Another surprise was the magnitude of the difference in CO2 loss rate from alkoxycarbonyloxyl radicals as compared with acyloxyl radicals. Their rapid 5-exo-cyclization was charted, as was their preferred spiro-cyclization onto aromatics. The first evidence that N-monosubstituted carbamoyloxyls had finite lifetimes was also forthcoming. It is evident that oxime derivatives have excellent credentials as reagents for radical generation and that there is ample room to extend their applications to additional radical types and for further heterocycle syntheses. There is also clear scope for the development of preparative procedures based around the alkoxyl and aminyl radicals that emerge downstream from oxime carbonate and oxime carbamate dissociations. PMID:24654991

Catalytic fixation of atmospheric carbon dioxide by copper(ii) complexes of bidentate ligands.

PubMed

Muthuramalingam, Sethuraman; Khamrang, Themmila; Velusamy, Marappan; Mayilmurugan, Ramasamy

2017-11-28

New copper(ii) complexes, [Cu(L1) 2 (H 2 O)](ClO 4 ) 2 , 1 [L1 = 2-pyridin-2-yl-quinoline], [Cu(L2) 2 (H 2 O)](ClO 4 ) 2 , 2 [L2 = 2-pyridin-2-yl-quinoxaline], [Cu(L3) 2 (H 2 O)](ClO 4 ) 2 , 3 [L3 = 6,7-dimethyl-2-pyridin-2-yl-quinoxaline], [Cu(L4) 2 (H 2 O)](ClO 4 ) 2 , 4 [L4 = 4-phenyl-2-pyridin-2-yl-quinoline] and [Cu(L5) 2 (H 2 O)](ClO 4 ) 2 , 5 [L5 = 4-phenyl-2-pyridin-2-yl-quinazoline], were synthesized and characterized as catalysts for selective fixation of atmospheric CO 2 . The molecular structure of 2 was determined by single-crystal X-ray studies and shown to have an unusual trigonal bipyramid geometry (τ, 0.936) around the copper(ii) center, with the coordination of two ligand units and a water molecule. The Cu-N quin (2.040, 2.048 Å) bonds are slightly longer than the Cu-N pyr (1.987 Å) bonds but shorter than the Cu-O water bond (2.117 Å). Well-defined Cu(ii)/Cu(i) redox potentials of around 0.352 to 0.401 V were observed for 1-5 in acetonitrile. The electronic absorption spectra of 1-5 showed ligand-based transitions at around 208-286 nm with a visible shoulder at around 342-370 nm. The d-d transitions appeared at around 750-800 and 930-955 nm in acetonitrile. The rhombic EPR spectra of 1-5 exhibited three different g values g x , 2.27-2.34; g y , 2.06-2.09; and g z , 1.95-1.98 at 70 K. Atmospheric CO 2 was successfully fixed by 1-5 using Et 3 N as a sacrificial reducing agent, resulting in CO 3 2- -bound complexes of type [Cu(L)CO 3 (H 2 O)] that display an absorption band at around 614-673 nm and a ν st at 1647 cm -1 . This CO 3 2- -bound complex of 1 was crystallized from the reaction mixture and it displayed a distorted square pyramidal geometry (τ, 0.369) around the copper(ii) center via the coordination of only one ligand unit, a carbonate group, and water molecules. Furthermore, treatment of the carbonate-bound Cu(ii) complexes with one equivalent of H + under N 2 atmosphere resulted in the liberation of bicarbonate (HCO 3 - ) and regenerated the parent complexes. These regenerated catalysts were active enough to fix CO 2 in eight repeating cycles without any change in efficiency. The fixation of CO 2 possibly occurs via the formation of Cu(i)-species, which is accompanied by the formation of an MLCT band at around 450-500 nm. The rates of Cu(i)-species formation, k obs , were determined and found to be 5.41-10.31 × 10 -3 s -1 in the presence of Et 3 N in acetonitrile at 25 °C. Interestingly, the copper(i)-species of 3 has been successfully crystallized and displayed a distorted tetrahedral geometry through the coordination of two units of ligand L3.