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Sample records for quinuclidines

  1. Antimicrobial activity of a quinuclidine-based FtsZ inhibitor and its synergistic potential with β-lactam antibiotics.

    PubMed

    Chan, Fung-Yi; Sun, Ning; Leung, Yun-Chung; Wong, Kwok-Yin

    2015-04-01

    Filamenting temperature-sensitive mutant Z (FtsZ) is an essential cell division protein that cooperates in the formation of the cytokinetic Z-ring in most bacteria and has thus been recognized as a promising antimicrobial drug target. We have recently used a structure-based virtual screening approach to identify pyrimidine-linked quinuclidines as a novel class of FtsZ inhibitors. In this study, we further investigated the antibacterial properties of one of the most potent compounds (quinuclidine 1) and its synergistic activity with β-lactam antibiotics. Susceptibility results showed that quinuclidine 1 was active against multiple antibiotic-resistant bacterial strains including methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecium with minimal inhibitory concentrations of 24 μg ml(-1). When quinuclidine 1 was combined with β-lactam antibiotics, synergistic antimicrobial activities against antibiotic-resistant strains of S. aureus were found. Further in vitro studies suggest that prevention of FtsZ protofilament formation by quinuclidine 1 impairs the formation of Z-ring, and thus inhibits bacterial division. These findings open a new approach for development of quinuclidine-based FtsZ inhibitors into potent antimicrobial agents. PMID:25293977

  2. Characterization of the intrinsic activity for a novel class of cannabinoid receptor ligands: Indole Quinuclidine analogues

    PubMed Central

    Franks, Lirit N.; Ford, Benjamin M.; Madadi, Nikhil R.; Penthala, Narsimha R.; Crooks, Peter A.; Prather, Paul L.

    2014-01-01

    Our laboratory recently reported that a group of novel indole quinuclidine analogues bind with nanomolar affinity to cannabinoid type-1 and type-2 receptors. This study characterized the intrinsic activity of these compounds by determining whether they exhibit agonist, antagonist, or inverse agonist activity at cannabinoid type-1 and/or type-2 receptors. Cannabinoid receptors activate Gi/Go-proteins that then proceed to inhibit activity of the downstream intracellular effector adenylyl cyclase. Therefore, intrinsic activity was quantified by measuring the ability of compounds to modulate levels of intracellular cAMP in intact cells. Concerning cannabinoid type-1 receptors endogenously expressed in Neuro2A cells, a single analogue exhibited agonist activity, while eight acted as neutral antagonists and two possessed inverse agonist activity. For cannabinoid type-2 receptors stably expressed in CHO cells, all but two analogues acted as agonists; these two exceptions exhibited inverse agonist activity. Confirming specificity at cannabinoid type-1 receptors, modulation of adenylyl cyclase activity by all proposed agonists and inverse agonists was blocked by co-incubation with the neutral cannabinoid type-1 antagonist O-2050. All proposed cannabinoid type-1 receptor antagonists attenuated adenylyl cyclase modulation by cannabinoid agonist CP-55,940. Specificity at cannabinoid type-2 receptors was confirmed by failure of all compounds to modulate adenylyl cyclase activity in CHO cells devoid of cannabinoid type-2 receptors. Further characterization of select analogues demonstrated concentration-dependent modulation of adenylyl cyclase activity with potencies similar to their respective affinities for cannabinoid receptors. Therefore, indole quinuclidines are a novel structural class of compounds exhibiting high affinity and a range of intrinsic activity at cannabinoid type-1 and type-2 receptors. PMID:24858620

  3. Antiangiogenic properties of substituted (Z)-(±)-2-(N-benzylindol-3-ylmethylene)quinuclidin-3-ol/one analogs and their derivatives.

    PubMed

    Venkateswaran, Amudhan; Reddy, Y Thirupathi; Sonar, Vijaykumar N; Muthusamy, Venkatraj; Crooks, Peter A; Freeman, Michael L; Sekhar, Konjeti R

    2010-12-15

    In the past half century research efforts have defined a critical role for angiogenesis in tumor growth and metastasis. We previously reported that inhibition of a novel target, ENOX1, by a (Z)-2-benzylindol-3-ylmethylene) quinuclidin-3-ol, suppressed tumor angiogenesis. The present study was undertaken in order to establish structure-activity relationships for quinuclidine analogs. The angiogenesis inhibiting activity of a series of substituted (Z)-(±)-2-(N-benzylindol-3-ylmethylene)quinuclidin-3-ols (1a-1k), (Z)-2-benzylindol-3-ylmethylene)quinuclidin-3-ones (2a-2h), (Z)-(±)-2-(1H/N-methyl-indol-3-ylmethylene)quinuclidin-3-ols (3a-3b), and substituted (Z)-(±)-2-(N-benzenesulfonylindol-3-yl-methylene)quinuclidin-3-ols and their derivatives (4a-4d) that incorporate a variety of substituents in both the indole and N-benzyl moieties was evaluated using Human Umbilical Vein Endothelial Cells (HUVECs) subjected to in vitro cell migration scratch assays, tubule formation in Matrigel, cell viability and proliferation assays. In total, 25 different analogs were evaluated. Based on in vitro cell migration scratch assays, eight analogs were identified as potent angiogenesis inhibitors at 10 μM, a concentration that was determined to be nontoxic by colony formation assay. In addition, this approach identified a potent antiangiogenic ENOX1 inhibitor, analog 4b. PMID:21055930

  4. Quinuclidine compounds differently act as agonists of Kenyon cell nicotinic acetylcholine receptors and induced distinct effect on insect ganglionic depolarizations.

    PubMed

    Mathé-Allainmat, Monique; Swale, Daniel; Leray, Xavier; Benzidane, Yassine; Lebreton, Jacques; Bloomquist, Jeffrey R; Thany, Steeve H

    2013-12-01

    We have recently demonstrated that a new quinuclidine benzamide compound named LMA10203 acted as an agonist of insect nicotinic acetylcholine receptors. Its specific pharmacological profile on cockroach dorsal unpaired median neurons (DUM) helped to identify alpha-bungarotoxin-insensitive nAChR2 receptors. In the present study, we tested its effect on cockroach Kenyon cells. We found that it induced an inward current demonstrating that it bounds to nicotinic acetylcholine receptors expressed on Kenyon cells. Interestingly, LMA10203-induced currents were completely blocked by the nicotinic antagonist α-bungarotoxin. We suggested that LMA10203 effect occurred through the activation of α-bungarotoxin-sensitive receptors and did not involve α-bungarotoxin-insensitive nAChR2, previously identified in DUM neurons. In addition, we have synthesized two new compounds, LMA10210 and LMA10211, and compared their effects on Kenyon cells. These compounds were members of the 3-quinuclidinyl benzamide or benzoate families. Interestingly, 1 mM LMA10210 was not able to induce an inward current on Kenyon cells compared to LMA10211. Similarly, we did not find any significant effect of LMA10210 on cockroach ganglionic depolarization, whereas these three compounds were able to induce an effect on the central nervous system of the third instar M. domestica larvae. Our data suggested that these three compounds could bind to distinct cockroach nicotinic acetylcholine receptors. PMID:23884575

  5. rac-(Z)-Methyl 1-benzyl-3-[(3-hy-droxy-quinuclidin-2-yl-idene)meth-yl]-1H-indole-6-carboxyl-ate.

    PubMed

    Penthala, Narsimha Reddy; Ponugoti, Purushotham Rao; Parkin, Sean; Crooks, Peter A

    2012-11-01

    In the title compound, C(25)H(26)N(2)O(3), the double bond connecting the aza-bicyclic and indole units has Z geometry. The compound was obtained as a racemate, and since the crystal is centrosymmetric it contains equal amounts of the S and R enanti-omers. However, the structure is disordered such that the asymmetric unit contains both enanti-omers in unequal amounts [refined occupancies 0.904 (2) and 0.096 (2)]. The dihedral angle between the benzene ring of the benzyl group and the mean plane of the indole ring is 76.07 (3) °. In the crystal, mol-ecules are linked by O-H⋯O(carbon-yl) hydrogen bonds into chains propagating in [110]. PMID:23284437

  6. Reactions of nitroxides XIII: Synthesis of the Morita–Baylis–Hillman adducts bearing a nitroxyl moiety using 4-acryloyloxy-2,2,6,6-tetramethylpiperidine-1-oxyl as a starting compound, and DABCO and quinuclidine as catalysts

    PubMed Central

    2012-01-01

    Summary The Morita–Baylis–Hillman adducts bearing a nitroxyl moiety were synthesized from 4-acryloyloxy-2,2,6,6-tetramethylpiperidine-1-oxyl and aliphatic, aryl and heterocyclic aldehydes. PMID:23019486

  7. Acetylcholine suppression and potential benefit against anticholinesterase poisoning. Annual report No. 2, 1 July 1983-30 June 1984

    SciTech Connect

    O'Neill, J.J.; Doukas, H.; Sterling, H.

    1984-07-01

    A new series of compounds containing the quinuclidine moiety has been synthesized and tested as inhibitors of brain choline acetyltransferase (ChAT) or as inhibitors of high affinity choline uptake (HAChU). The tertiary quinuclidine was incorporated because of the potency it confers on anticholinergic compounds and antimuscarinic drugs, such as quinuclidinylbenzilate (QNB). Structure-activity studies indicate that ChAT inhibition and lipophilicity show a direct correlation and that some of the structure-activity relationships previously proposed (2) need to be modified to fit new insights gained from studies with the brain ChAT. The effectiveness of the quaternary HAChU inhibitor, acetylseco-hemicholinium (AcSeco HC) to block choline uptake and interfere with acetylcholine (ACh) synthesis served as a basis for in vivo protection studies versus soman. As an adjunct to atropine and oxime, the results obtained point to the need for HAChU inhibitors with pharmacokinetic properties which will permit oral or parenteral administration leading to high central nervous system (CNS) penetration. Based on initial in vitro studies, several quinuclidine derivatives show activity in brain nerve ending preparations. A series of toxicity studies has established the LD50 dose of soman at 1 hr and 24 hours. Based on the most potent inhibitors of ChAT activity, we have selected a series of tertiary amines as adjuncts to atropine-oxime therapy to ascertain whether such combinations increase protection against soman.

  8. Multiple Pharmacophores for the Selective Activation of Nicotinic α7-Type Acetylcholine Receptors

    PubMed Central

    Horenstein, Nicole A.; Leonik, Fedra M.; Papke, Roger L.

    2010-01-01

    The activation of heteromeric and homomeric nicotinic acetylcholine receptors was studied in Xenopus laevis oocytes to identify key structures of putative agonist molecules associated with the selective activation of homomeric α7 receptors. We observed that selectivity between α7 and α4β2 was more readily obtained than selectivity between α7 and α3β4. Based on structural comparisons of previously characterized selective and nonselective agonists, we hypothesize at least three chemical motifs exist that, when present in molecules containing an appropriate cationic center, could be associated with the selective activation of α7 receptors. We identify the three distinct structural motifs based on prototypical drugs as the choline motif, the tropane motif, and the benzylidene motif. The choline motif involves the location of an oxygen-containing polar group such as a hydroxyl or carbonyl separated by two carbons from the charged nitrogen. The tropane motif provides α7-selectivity based on the addition of multiple small hydrophobic groups positioned away from the cationic center in specific orientations. We show that this motif can convert the nonselective agonists quinuclidine and ethyltrimethyl-ammonium to the α7-selective analogs methyl-quinuclidine and diethyldimethyl-ammonium, respectively. We have shown previously that the benzylidene group of 3–2,4, dimethoxy-benzylidene anabaseine (GTS-21) converts anabaseine into an α7-selective agonist. The benzylidene motif was also applied to quinuclidine to generate another distinct family of α7-selective agonists. Our results provide insight for the further development of nicotinic therapeutics and will be useful to direct future experiments with protein structure-based modeling and site-directed mutagenesis. PMID:18768388

  9. Organic transformations catalyzed by methylrhenium trioxide

    SciTech Connect

    Zhu, Z.

    1995-11-01

    Methylrhenium trioxide (MTO), CH{sub 3}ReO{sub 3}, was first prepared in 1979. MTO forms stable or unstable adducts with electron-rich ligands, such as amines (quinuclidine, 1,4-diazabicyclo-octane, pyridine, aniline, 2,2{prime}-bipyridine), alkynes, olefins, 1,2-diols, catechols, hydrogen peroxide, water, thiophenols, 1,2-dithiols, triphenylphosphine, 2-aminophenols, 2-aminothiophenols, 8-hydroxyquinoline and halides (Cl-, Br-, I-). After coordination, different further reactions will occur for different reagents. Reactions described in this report include the dehydration of alcohols, direct amination of alcohols, activation of hydrogen peroxide, oxygen transfer, and decomposition of ethyl diazoacetate.

  10. Amine-Catalyzed Asymmetric (3 + 3) Annulations of β'-Acetoxy Allenoates: Enantioselective Synthesis of 4H-Pyrans.

    PubMed

    Ni, Chunjie; Tong, Xiaofeng

    2016-06-29

    The asymmetric (3 + 3) annulations of β'-acetoxy allenoates with either 3-oxo-nitriles or pyrazolones have been realized by using 6'-deoxy-6'-[(l)-N,N-(2,2'-oxidiethyl)-valine amido]quinine (6h) as the catalyst. The three functions of catalyst 6h, including Lewis base (quinuclidine N), H-bond donor (amide NH), and Brønsted base (morpholine N), cooperatively take crucial roles on the chemo- and enantioselectivity, allowing for the construction of 4H-pyran and 4H-pyrano[2,3-c]pyrazole in high yields and enantioselectivity. PMID:27310820

  11. Chiral modification of platinum: ab initio study of the effect of hydrogen coadsorption on stability and geometry of adsorbed cinchona alkaloids.

    PubMed

    Hahn, Konstanze R; Seitsonen, Ari P; Baiker, Alfons

    2015-11-01

    The cinchona alkaloids cinchonidine and cinchonine belong to the most efficient chiral modifiers for the noble metal-catalyzed enantioselective hydrogenation of C=O and C=C bonds. Under reaction conditions these modifiers are coadsorbed on the noble metal surface with hydrogen. Using density functional theory, we studied the effect of coadsorbed hydrogen on the adsorption mode of cinchonidine and cinchonine on a Pt(111) surface at different hydrogen coverages. The theoretical study indicates that the presence of coadsorbed hydrogen affects both the adsorption geometry as well as the stability of the adsorbed cinchona alkaloids. At all hydrogen coverages the cinchona alkaloids are found to be adsorbed via anchoring of the quinoline moiety. In the absence of hydrogen as well as at low hydrogen coverage the quinoline moiety adsorbs nearly parallel to the surface, whereas at higher hydrogen coverage it becomes tilted. Higher hydrogen coverage as well as partial hydrogenation of the quinoline part of the cinchona alkaloid and hydrogen transfer to the C[double bond, length as m-dash]C double bond at 10, 11 position of the quinuclidine moiety destabilize the adsorbed cinchona alkaloid, whereas hydrogen transfer to the nitrogen atom of the quinoline and the quinuclidine moiety stabilizes the adsorbed molecule. The stability as well as the adsorption geometry of the cinchona alkaloids are affected by the coadsorbed hydrogen and are proposed to influence the efficiency of the enantiodifferentiating ability of the chirally modified platinum surface. PMID:26426825

  12. Squalene Synthase As a Target for Chagas Disease Therapeutics

    PubMed Central

    Chan, Hsiu-Chien; Li, Jikun; Zheng, Yingying; Huang, Chun-Hsiang; Ren, Feifei; Chen, Chun-Chi; Zhu, Zhen; Galizzi, Melina; Li, Zhu-Hong; Rodrigues-Poveda, Carlos A.; Gonzalez-Pacanowska, Dolores; Veiga-Santos, Phercyles; de Carvalho, Tecia Maria Ulisses; de Souza, Wanderley; Urbina, Julio A.; Wang, Andrew H.-J.; Docampo, Roberto; Li, Kai; Liu, Yi-Liang; Oldfield, Eric; Guo, Rey-Ting

    2014-01-01

    Trypanosomatid parasites are the causative agents of many neglected tropical diseases and there is currently considerable interest in targeting endogenous sterol biosynthesis in these organisms as a route to the development of novel anti-infective drugs. Here, we report the first x-ray crystallographic structures of the enzyme squalene synthase (SQS) from a trypanosomatid parasite, Trypanosoma cruzi, the causative agent of Chagas disease. We obtained five structures of T. cruzi SQS and eight structures of human SQS with four classes of inhibitors: the substrate-analog S-thiolo-farnesyl diphosphate, the quinuclidines E5700 and ER119884, several lipophilic bisphosphonates, and the thiocyanate WC-9, with the structures of the two very potent quinuclidines suggesting strategies for selective inhibitor development. We also show that the lipophilic bisphosphonates have low nM activity against T. cruzi and inhibit endogenous sterol biosynthesis and that E5700 acts synergistically with the azole drug, posaconazole. The determination of the structures of trypanosomatid and human SQS enzymes with a diverse set of inhibitors active in cells provides insights into SQS inhibition, of interest in the context of the development of drugs against Chagas disease. PMID:24789335

  13. trans-Symmetric Dynamic Covalent Systems: Connected Transamination and Transimination Reactions

    PubMed Central

    Schaufelberger, Fredrik; Hu, Lei; Ramström, Olof

    2015-01-01

    The development of chemical transaminations as a new type of dynamic covalent reaction is described. The key 1,3-proton shift is under complete catalytic control and can be conducted orthogonally to, or simultaneous with, transimination in the presence of an amine to rapidly yield two-dimensional dynamic systems with a high degree of complexity evolution. The transamination–transimination systems are proven to be fully reversible, stable over several days, compatible with a range of functional groups, and highly tunable. Kinetic studies show transamination to be the rate-limiting reaction in the network. Furthermore, it was discovered that readily available quinuclidine is a highly potent catalyst for aldimine transaminations. This study demonstrates how connected dynamic reactions give rise to significantly larger systems than the unconnected counterparts, and shows how reversible isomerizations can be utilized as an effective diversity-generating element. PMID:26044061

  14. Salts of phenylacetic acid and 4-hydroxyphenylacetic acid with Cinchona alkaloids: Crystal structures, thermal analysis and FTIR spectroscopy

    NASA Astrophysics Data System (ADS)

    Amombo Noa, Francoise M.; Jacobs, Ayesha

    2016-06-01

    Seven salts were formed with phenylacetic acid (PAA), 4-hydroxyphenylacetic acid (HPAA) and the Cinchona alkaloids; cinchonidine (CIND), quinidine (QUID) and quinine (QUIN). For all the structures the proton was transferred from the carboxylic acid of the PAA/HPAA to the quinuclidine nitrogen of the respective Cinchona alkaloid. For six of the salts, water was included in the crystal structures with one of these also incorporating an isopropanol solvent molecule. However HPAA co-crystallised with quinine to form an anhydrous salt, (HPAA-)(QUIN+). The thermal stability of the salts were determined and differential scanning calorimetry revealed that the (HPAA-)(QUIN+) salt had the highest thermal stability compared to the other salt hydrates. The salts were also characterized using Fourier transform infrared spectroscopy. (PAA-)(QUID+)·H2O and (PAA-)(QUIN+)·H2O are isostructural and Hirshfeld surface analysis was completed to compare the intermolecular interactions in these two structures.

  15. Dimeric Cinchona alkaloids.

    PubMed

    Boratyński, Przemysław J

    2015-05-01

    Nature is full of dimeric alkaloids of various types from many plant families, some of them with interesting biological properties. However, dimeric Cinchona alkaloids were not isolated from any species but were products of designed partial chemical synthesis. Although the Cinchona bark is amongst the sources of oldest efficient medicines, the synthetic dimers found most use in the field of asymmetric synthesis. Prominent examples include the Sharpless dihydroxylation and aminohydroxylation ligands, and dimeric phase transfer catalysts. In this article the syntheses of Cinchona alkaloid dimers and oligomers are reviewed, and their structure and applications are outlined. Various synthetic routes exploit reactivity of the alkaloids at the central 9-hydroxyl group, quinuclidine, and quinoline rings, as well as 3-vinyl group. This availability of reactive sites, in combination with a plethora of linker molecules, contributes to the diversity of the products obtained. PMID:25586655

  16. Controlled synthesis of polyenes by catalytic methods. Progress report, December 1, 1989--November 30, 1992

    SciTech Connect

    Schrock, R.R.

    1992-07-01

    A more direct approach to polyenes by the direct polymerization of acetylenes has been achieved. We were able to show that polymerization of acetylene itself can be controlled with a well- characterized alkylidene catalyst, but only if a base such as quinuclidine is present in order to slow down the rate of propagation relative to initiation. (Quinuclidine may also stabilize vinylalkylidene intermediates formed in the reaction). Unfortunately, ``living polyenes`` were no more stable than isolated polyenes, and so this approach had its limitations. Direct polymerization of acetylene by Mo(CH-t-Bu)(NAr)(O-t-Bu){sub 2} was more successful, but inherent polyene instability was still a problem. The most important result of the past grant period is the finding that dipropargyl derivatives (HC=CCH{sub 2}XCH{sub 2}C=CH; X = CH{sub 2}, C(CO{sub 2}R){sub 2}, SiR{sub 2}, etc.), which have been reported to be cyclopolymerized by various classical catalysts by as yet unknown mechanisms, are polymerized by Mo(CH-t-Bu)(NAr)[OCMe(CF{sub 3}){sub 2}]{sub 2} in dimethoxyethane. We speculate that intramolecular formation of a five-membered ring in the product of {alpha} addition is fast enough to yield another terminal alkylidene on the time scale of the polymerization reaction, while a six-membered ring is formed in a reaction involving a more reaction terminal alkylidene. Either intermediate alkylidene, but most likely the terminal alkylidene, could react with additional monomer to lead to growth of a chain having ``dangling`` triple bonds that eventually could be employed to form crosslinks.

  17. Thermochemistry of Alane Complexes for Hydrogen Storage: A Theoretical and Experimental Investigation

    PubMed Central

    2011-01-01

    Knowledge of the relative stabilities of alane (AlH3) complexes with electron donors is essential for identifying hydrogen storage materials for vehicular applications that can be regenerated by off-board methods; however, almost no thermodynamic data are available to make this assessment. To fill this gap, we employed the G4(MP2) method to determine heats of formation, entropies, and Gibbs free energies of formation for 38 alane complexes with NH3−nRn (R = Me, Et; n = 0−3), pyridine, pyrazine, triethylenediamine (TEDA), quinuclidine, OH2−nRn (R = Me, Et; n = 0−2), dioxane, and tetrahydrofuran (THF). Monomer, bis, and selected dimer complex geometries were considered. Using these data, we computed the thermodynamics of the key formation and dehydrogenation reactions that would occur during hydrogen delivery and alane regeneration, from which trends in complex stability were identified. These predictions were tested by synthesizing six amine−alane complexes involving trimethylamine, triethylamine, dimethylethylamine, TEDA, quinuclidine, and hexamine and obtaining upper limits of ΔG° for their formation from metallic aluminum. Combining these computational and experimental results, we establish a criterion for complex stability relevant to hydrogen storage that can be used to assess potential ligands prior to attempting synthesis of the alane complex. On the basis of this, we conclude that only a subset of the tertiary amine complexes considered and none of the ether complexes can be successfully formed by direct reaction with aluminum and regenerated in an alane-based hydrogen storage system. PMID:22962624

  18. Neuropharmacokinetics of two investigational compounds in rats: divergent temporal profiles in the brain and cerebrospinal fluid.

    PubMed

    Tang, Cuyue; Chen, Ting; Kapadnis, Sudarshan; Hodgdon, Hilliary; Tao, Yi; Chen, Xing; Wen, Melody; Costa, Don; Murphy, Deirdre; Nolan, Scott; Flood, Dorothy G; Welty, Devin F; Koenig, Gerhard

    2014-10-15

    Two investigational compounds (FRM-1, (R)-7-fluoro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide and FRM-2, (R)-7-cyano-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide) resided in rat brain longer than in systemic circulation. In Caco-2 directional transport studies, they both showed good intrinsic passive permeability but differed significantly in efflux susceptibility (efflux ratio of <2 and ∼7, respectively), largely attributed to P-glycoprotein (P-gp). Capitalizing on these interesting properties, we investigated how cerebrospinal fluid (CSF) concentration (CCSF) would be shaped by unbound plasma concentration (Cu,p) and unbound brain concentration (Cu,b) in disequilibrium conditions and at steady state. Following subcutaneous administration, FRM-1CCSF largely followed Cu,p initially and leveled between Cu,p and Cu,b. However, it gradually approached Cu,b and became lower than, but parallel to Cu,b at the terminal phase. In contrast, FRM-2CCSF temporal profile mostly paralleled the Cu,p but was at a much lower level. Upon intravenous infusion to steady state, FRM-1CCSF and Cu,b were similar, accounting for 61% and 69% of the Cu,p, indicating a case of largely passive diffusion-governed brain penetration where CCSF served as a good surrogate for Cu,b. On the contrary, FRM-2CCSF and Cu,b were remarkably lower than Cu,p (17% and 8% of Cu,p, respectively), suggesting that FRM-2 brain penetration was severely impaired by P-gp-mediated efflux and CCSF underestimated this impact. A semi-physiologically based pharmacokinetic (PBPK) model was constructed that adequately described the temporal profiles of the compounds in the plasma, brain and CSF. Our work provided some insight into the relative importance of blood-brain barrier (BBB) and blood-CSF barrier (BCSFB) in modulating CCSF. PMID:25091561

  19. Enantioselective hydrogenation. IV. Hydrogen isotope exchange in 10,11-dihydrocinchonidine and in quinoline catalyzed by platinum group metals

    SciTech Connect

    Bond, G.; Wells, P.B.

    1994-12-01

    Hydrogen isotope (H/D) exchange in the alkaloid 10,11-dihydrocinchonidine has been studied over 6.4% Pt/silica (EUROPT-1), 5% Ru/alumina, 5% Rh/alumina, and 5% Pd/alumina at 293 K using C{sub 2}H{sub 5}OD and D{sub 2} as solvent and deuterium source. Exchange was accompanied by hydrogenation. Over Pt, fast exchange occurred in the hydroxyl group followed by multiple exchange in which alkaloid molecules containing, 2, 3, 4 and 5 deuterium atoms were formed simultaneously. Mass spectrometry and {sup 1}H NMR showed that this multiple exchange occurred in the quinoline ring system and at C{sub 9}, but not in the quinuclidine ring system. The pattern of exchange in Ru was similar. Over Rh extensive hydrogenolysis of the quinuclidine ring system occurred, and over Pd the quinoline ring system was rapidly hydrogenated. Quinoline exchange and hydrogenation were also studied at 293 K; relatively rapid exchange occurred over Pt, Ru, and Rh, particularly at the 2- and 8-positions, whereas hydrogenation without significant exchange occurred over Pd. 10,11-Dihydrocinchonidine is adsorbed on Pt and Ru via the quinoline ring system and the multiple nature of the exchange indicates that the quinoline moiety is adsorbed approximately parallel to the metal surface by multicenter {pi}-bonding. An additional interaction of the alkaloid molecule with the surface occurs at carbon atom C{sub 9}, which may interpret the slower exchange in the alkaloid by comparison with that in quinoline. This study supports and enhances the model proposed to interpret the origin of enantioselectivity in pyruvate hydrogenation over Pt and Ir modified by cinchona alkaloids. The similarities of exchange over Pt and Ru suggest that enantioselective catalysis should be achievable over Ru. 28 refs., 2 figs., 2 tabs.

  20. Controlled Synthesis of Polyenes by Catalytic Methods. Progress Report, December 1, 1989 -- November 30, 1992

    DOE R&D Accomplishments Database

    Schrock, R. R.

    1992-01-01

    A more direct approach to polyenes by the direct polymerization of acetylenes has been achieved. We were able to show that polymerization of acetylene itself can be controlled with a well- characterized alkylidene catalyst, but only if a base such as quinuclidine is present in order to slow down the rate of propagation relative to initiation. (Quinuclidine may also stabilize vinylalkylidene intermediates formed in the reaction). Unfortunately, living polyenes were no more stable than isolated polyenes, and so this approach had its limitations. Direct polymerization of acetylene by Mo(CH-t-Bu)(NAr)(O-t-Bu){sub 2} was more successful, but inherent polyene instability was still a problem. The most important result of the past grant period is the finding that dipropargyl derivatives (HC=CCH{sub 2}XCH{sub 2}C=CH; X = CH{sub 2}, C(CO{sub 2}R){sub 2}, SiR{sub 2}, etc.), which have been reported to be cyclopolymerized by various classical catalysts by as yet unknown mechanisms, are polymerized by Mo(CH-t-Bu)(NAr)[OCMe(CF{sub 3}){sub 2}]{sub 2} in dimethoxyethane. We speculate that intramolecular formation of a five-membered ring in the product of {alpha} addition is fast enough to yield another terminal alkylidene on the time scale of the polymerization reaction, while a six-membered ring is formed in a reaction involving a more reaction terminal alkylidene. Either intermediate alkylidene, but most likely the terminal alkylidene, could react with additional monomer to lead to growth of a chain having dangling triple bonds that eventually could be employed to form crosslinks.

  1. Multiphoton ionization-fragmentation patterns of tertiary amines

    NASA Astrophysics Data System (ADS)

    Parker, D. H.; Bernstein, R. B.; Lichtin, D. A.

    1981-09-01

    Multiphoton ionization (MPI)-fragmentation patterns are reported for a series of normal and caged tertiary amines. Ionization is enhanced by two-photon resonance with the 3s and 3p Rydberg states of trimethylamine, triethylamine, and the caged amines quinuclidine and triethylenediamine. Over the wavelength region λ = 400-530 nm, N(CH3)3 ionizes to the parent ion (P) and fragments only by the loss of a H atom to yield the P-H daughter ion; N(C2H5)3 ionizes to its parent ion and fragments by the loss of a methyl to form the P-CH3 ion. The branching ratio of daughter to parent ions is found to be essentially independent of laser intensity but strongly dependent on laser wavelength. The caged amines quinuclidine [N(C2H4)3CH, or ABCO] and triethylenediamine [N(C2H4)3N, or DABCO] fragment extensively over this λ range in a manner dependent on both laser wavelength and intensity. The extent of daughter ion formation in N(CH3)3 and N(C2H5)3 can be understood by consideration of the wavelength regions in which the total available energy from the initial three- or four-photon ionization event exceeds the appearance potential of the given daughter ion. For the caged amines direct observation of this mechanism is masked by fragmentation due to sequential absorption of photons (during the ˜5 ns pulse duration) by the parent and/or daughter ions. The present results show that even for molecules with broad, unstructured UV absorption and MPI spectra such as N(CH3)3 and N(C2H5)3, considerable information on photon-molecule and photon-ion interactions can still be gained by the MPI mass spectrometry technique.

  2. Thermochemistry of Alane Complexes for Hydrogen Storage: A Theoretical and Experimental Investigation

    SciTech Connect

    Wong, B.M.; Graetz, J.; Lacina, D.; Nielsen, I.M.B.; Allendorf, M.D.

    2011-03-30

    Knowledge of the relative stabilities of alane (AlH{sub 3}) complexes with electron donors is essential for identifying hydrogen storage materials for vehicular applications that can be regenerated by off-board methods; however, almost no thermodynamic data are available to make this assessment. To fill this gap, we employed the G4(MP2) method to determine heats of formation, entropies, and Gibbs free energies of formation for 38 alane complexes with NH{sub 3-n}R{sub n} (R = Me, Et; n = 0-3), pyridine, pyrazine, triethylenediamine (TEDA), quinuclidine, OH{sub 2-n}R{sub n} (R = Me, Et; n = 0-2), dioxane, and tetrahydrofuran (THF). Monomer, bis, and selected dimer complex geometries were considered. Using these data, we computed the thermodynamics of the key formation and dehydrogenation reactions that would occur during hydrogen delivery and alane regeneration, from which trends in complex stability were identified. These predictions were tested by synthesizing six amine-alane complexes involving trimethylamine, triethylamine, dimethylethylamine, TEDA, quinuclidine, and hexamine and obtaining upper limits of {Delta}G{sup o} for their formation from metallic aluminum. Combining these computational and experimental results, we establish a criterion for complex stability relevant to hydrogen storage that can be used to assess potential ligands prior to attempting synthesis of the alane complex. On the basis of this, we conclude that only a subset of the tertiary amine complexes considered and none of the ether complexes can be successfully formed by direct reaction with aluminum and regenerated in an alane-based hydrogen storage system.

  3. Structure-property relationship of quinuclidinium surfactants--Towards multifunctional biologically active molecules.

    PubMed

    Skočibušić, Mirjana; Odžak, Renata; Štefanić, Zoran; Križić, Ivana; Krišto, Lucija; Jović, Ozren; Hrenar, Tomica; Primožič, Ines; Jurašin, Darija

    2016-04-01

    Motivated by diverse biological and pharmacological activity of quinuclidine and oxime compounds we have synthesized and characterized novel class of surfactants, 3-hydroxyimino quinuclidinium bromides with different alkyl chains lengths (CnQNOH; n=12, 14 and 16). The incorporation of non conventional hydroxyimino quinuclidinium headgroup and variation in alkyl chain length affects hydrophilic-hydrophobic balance of surfactant molecule and thereby physicochemical properties important for its application. Therefore, newly synthesized surfactants were characterized by the combination of different experimental techniques: X-ray analysis, potentiometry, electrical conductivity, surface tension and dynamic light scattering measurements, as well as antimicrobial susceptibility tests. Comprehensive investigation of CnQNOH surfactants enabled insight into structure-property relationship i.e., way in which the arrangement of surfactant molecules in the crystal phase correlates with their solution behavior and biologically activity. The synthesized CnQNOH surfactants exhibited high adsorption efficiency and relatively low critical micelle concentrations. In addition, all investigated compounds showed very potent and promising activity against Gram-positive and clinically relevant Gram-negative bacterial strains compared to conventional antimicrobial agents: tetracycline and gentamicin. The overall results indicate that bicyclic headgroup with oxime moiety, which affects both hydrophilicity and hydrophobicity of CnQNOH molecule in addition to enabling hydrogen bonding, has dominant effect on crystal packing and physicochemical properties. The unique structural features of cationic surfactants with hydroxyimino quinuclidine headgroup along with diverse biological activity have made them promising structures in novel drug discovery. Obtained fundamental understanding how combination of different functionalities in a single surfactant molecule affects its physicochemical

  4. The Minimal Pharmacophore for Silent Agonism of the α7 Nicotinic Acetylcholine Receptor

    PubMed Central

    Chojnacka, Kinga; Horenstein, Nicole A.

    2014-01-01

    The minimum pharmacophore for activation of the human α7 nicotinic acetylcholine receptor (nAChR) is the tetramethylammonium cation. Previous work demonstrated that larger quaternary ammonium compounds, such as diethyldimethylammonium or 1-methyl quinuclidine, were α7-selective partial agonists, but additional increase in the size of the ammonium cation or the quinuclidine N-alkyl group by a single carbon to an N-ethyl group led to a loss of efficacy for ion channel activation. We report that although such compounds are ineffective at inducing the normal channel open state, they nonetheless regulate the induction of specific conformational states normally considered downstream of channel activation. We synthesized several panels of quaternary ammonium nAChR ligands that systematically varied the size of the substituents bonded to the central positively charged nitrogen atom. In these molecular series, we found a correlation between the molecular volume of the ligand and/or charge density, and the receptor’s preferred distribution among conformational states including the closed state, the active state, a nonconducting state that could be converted to an activated state by a positive allosteric modulator (PAM), and a PAM-insensitive nonconducting state. We hypothesize that the changes of molecular volume of an agonist’s cationic core subtly impact interactions at the subunit interface constituting the orthosteric binding site in such a way as to regulate the probability of conversions among the conformational states. We define a new minimal pharmacophore for the class of compounds we have termed “silent agonists,” which are able to induce allosteric modulator-dependent activation but not the normal activated state. PMID:24990939

  5. Reactions of hypochlorous acid with biological substrates are activated catalytically by tertiary amines.

    PubMed

    Prütz, W A

    1998-09-15

    The activation of reactions of HOCl with a variety of model substrates by tertiary amines was investigated spectroscopically by tandem-mix and stopped-flow techniques. HOCl-induced chlorination of salicylate can be sped up by several orders of magnitude by catalytic amounts of trimethylamine (TMN). The effect is obviously due to the fast generation of reactive quarternary chloramonium ions, TMN+ Cl, which act as chain carrier in a catalytic reaction cycle. Of various catalysts tested, quinine shows the highest activity; this is attributable to the quinuclidine (QN) substituent, a bicyclic tertiary amine, forming a particularly reactive chloro derivative, QN+ Cl, which does not decompose autocatalytically. The rate of catalytic salicylate chlorination as a function of pH (around pH 7) depends not at least on the basicity of the tertiary amine; the rate increases with pH in the cases of TMN and quinuclidine (high basicity), but decreases with pH in the case of MES (low basicity). Tertiary amines also catalyze the interaction between HOCl and alkenes, as shown using sorbate as model. Reaction of HOCl with the nucleotides GMP and CMP is sped up remarkably by catalytic amounts of tertiary amines. In the case of GMP the same product spectrum is produced by HOCl in absence and presence of catalyst, but a change in the product spectra is obtained when AMP and CMP are reacted with HOCl in presence of catalyst. Using poly(dA-dT).poly(dA-dT) as DNA model, it is shown that HOCl primarily induces an absorbance increase at 263 nm, which indicates unfolding of the double strand due to fast chlorination of thymidine; a subsequent secondary absorbance decrease can be explained by slow chlorination of adenosine. Both the primary and secondary processes are activated by catalytic amounts of quinine. No evidence was found for a radical pathway in TMN-mediated oxidation of formate by HOCl. The present results suggest that low concentrations of certain tertiary amines have the potential

  6. Size Effects on the Magnetic Properties of Nanoscale Particles

    NASA Astrophysics Data System (ADS)

    Chen, Jianping

    %, and 10% by quinuclidine, pyridine and carbon monoxide, respectively. The ligands affects the core and shell of the particles in different ways. Quinuclidine and pyridine only affected the shell phase while carbon monoxide affects both. The quenching effect was qualitatively explained by the interaction between ligand and surface Co atoms, which in turn changes the electron configuration in the 3d band of the Co particles.

  7. [Use of antihistamines in a physician's clinical practice].

    PubMed

    Luss, L V

    2014-01-01

    Histamine that belongs to one of the most important mediators involved in the regulation of the body's vital functions plays a great role in the pathogenesis of different diseases. Histamine is released during inflammatory and allergic reactions, anaphylactic and anaphylactoid shock, pseudoallergic reactions, and others. Acting through histamine receptors, it leads to increased intracellular concentration of cyclic guanosine monophosphate, enhanced chemotaxis of eosinophils and neutrophils, production of prostaglandins and thromboxane B, suppressed synthesis of lymphokines, etc. and causes contraction of smooth muscles of particularly the bronchi and intestine, dilation of vessels and their increased permeability, mucus hypersecretion in the upper airways, lower blood pressure, angioedema and itch, etc. In this connection, antihistamines that block histamine-induced reactions in various ways: by inhibiting its biosynthesis, enhancing its neutralization, blocking the access to receptors, and suppressing the release from mast cells, occupy a prominent place in clinical practice. The review covers the classification, main mechanisms of pharmacological action, and indications for the use of antihistamines that not only have the well-known antihistamine properties, but have also a broad spectrum of anti-inflammatory activity. There are data on the benefits of a group of antihistamines, the quinuclidine derivatives (quifenadine, sequifenadine) that were designed by Academician M.D. Mashkovsky and are one of the first examples of designing new classes of multifunctional non-sedating antihistamines, which combines a high selective activity to block histamine type 1 receptors and an ability to block serotonin and to break down histamine directly in tissues. PMID:25306755

  8. Hydrogen bonding and molecular association in 2-(quinuclidinium)-butyric acid bromide hydrate studied by X-ray diffraction, DFT calculations, FTIR and NMR spectroscopy, and potentiometric titration

    NASA Astrophysics Data System (ADS)

    Dega-Szafran, Z.; Katrusiak, A.; Szafran, M.; Barczyński, P.

    2010-06-01

    The structure of 2-(quinuclidinium)-butyric acid bromide hydrate (QNBu·H 2O·HBr, 3) has been determined by X-ray diffraction, DFT calculations and characterized by FTIR and NMR spectroscopy. Crystals of 3 are monoclinic, space group P2 1. The water molecule interacts with the carboxylic group of 2-(quinuclidinium)-butyric acid and with the bromide anion by the COOH⋯OH 2 and HOH⋯Br hydrogen bonds of 2.575(3) and 3.293(2) Å, respectively. The structures of monomer ( 4) and dimeric cation ( 5) of the title complex have been optimized by the B3LYP/6-31G(d,p) approach, yielding conformations consistent with this in the crystal. The solid-state FTIR spectra of 3 and its deuterated analogue have been measured and compared with the theoretical spectrum of 4. The assignments of the observed and predicted bands have been proposed. The molecule of 3 has a chiral center at the C(9) atom, which is responsible for the non-magnetically equivalence of the α-ring and C(11)H 2 methylene protons in 1H NMR spectrum. The values of p Ka of quinuclidinium-acetate (quinuclidine betaine), 2-(quinuclidinium)-propionate and 2-(quinuclidinium)-butyrate have been determined by the potentiometric titration of their hydrohalides.

  9. Diastereodivergent asymmetric sulfa-Michael additions of α-branched enones using a single chiral organic catalyst.

    PubMed

    Tian, Xu; Cassani, Carlo; Liu, Yankai; Moran, Antonio; Urakawa, Atsushi; Galzerano, Patrizia; Arceo, Elena; Melchiorre, Paolo

    2011-11-01

    A significant limitation of modern asymmetric catalysis is that, when applied to processes that generate chiral molecules with multiple stereogenic centers in a single step, researchers cannot selectively access the full matrix of all possible stereoisomeric products. Mirror image products can be discretely provided by the enantiomeric pair of a chiral catalyst. But modulating the enforced sense of diastereoselectivity using a single catalyst is a largely unmet challenge. We document here the possibility of switching the catalytic functions of a chiral organic small molecule (a quinuclidine derivative with a pendant primary amine) by applying an external chemical stimulus, in order to induce diastereodivergent pathways. The strategy can fully control the stereochemistry of the asymmetric conjugate addition of alkyl thiols to α-substituted α,β-unsaturated ketones, a class of carbonyls that has never before succumbed to a catalytic approach. The judicious choice of acidic additives and reaction media switches the sense of the catalyst's diastereoselection, thereby affording either the syn or anti product with high enantioselectivity. PMID:21936561

  10. Synthesis of a new series of dithiocarbamates with effective human carbonic anhydrase inhibitory activity and antiglaucoma action.

    PubMed

    Bozdag, Murat; Carta, Fabrizio; Vullo, Daniela; Akdemir, Atilla; Isik, Semra; Lanzi, Cecilia; Scozzafava, Andrea; Masini, Emanuela; Supuran, Claudiu T

    2015-05-15

    A new series of dithiocarbamates (DTCs) was prepared from primary/secondary amines incorporating amino/hydroxyl-alkyl, mono- and bicyclic aliphatic ring systems based on the quinuclidine, piperidine, hydroxy-/carboxy-/amino-substituted piperidine, morpholine and piperazine scaffolds, and carbon disulfide. The compounds were investigated for the inhibition of four mammalian α-carbonic anhydrases (CAs, EC 4.2.1.1) of pharmacologic relevance, that is, the human (h) hCA I, II, IX and XII, drug targets for antiglaucoma (hCA II and XII) or antitumor (hCA IX/XII) agents. The compounds were moderate or inefficient hCA I inhibitors (off-target isoform for both applications), efficiently inhibited hCA II, whereas some of them were low nanomolar/subnanomolar hCA IX/XII inhibitors. One DTC showed excellent intraocular pressure (IOP) lowering properties in an animal model of glaucoma, with a two times better efficiency compared to the clinically used sulfonamide dorzolamide. PMID:25846066

  11. Dithiocarbamates with potent inhibitory activity against the Saccharomyces cerevisiae β-carbonic anhydrase.

    PubMed

    Bozdag, Murat; Carta, Fabrizio; Vullo, Daniela; Isik, Semra; AlOthman, Zeid; Osman, Sameh M; Scozzafava, Andrea; Supuran, Claudiu T

    2016-01-01

    Dithiocarbamates (DTCs) prepared from primary or secondary amines, which incorporated amino/hydroxyl-alkyl, mono-/bicyclic aliphatic/heterocyclic rings based on the quinuclidine, piperidine, hydroxy-/carboxy-/amino-substituted piperidine, morpholine and piperazine scaffolds, were investigated for the inhibition of α- and β-carbonic anhydrases (CAs, EC 4.2.1.1) of pharmacologic relevance, such as the human (h) isoform hCA I and II, as well as the Saccharomyces cerevisiae β-CA, scCA. The yeast and its β-CA were shown earlier to be useful models of pathogenic fungal infections. The DTCs investigated here were medium potency hCA I inhibitors (K(I)s of 66.5-910 nM), were more effective as hCA II inhibitors (K(I)s of 8.9-107 nM) and some of them showed excellent, low nanomolar activity against the yeast enzyme, with inhibition constants ranging between 6.4 and 259 nM. The detailed structure activity relationship for inhibition of the yeast and human enzymes is discussed. Several of the investigated DTCs showed excellent selectivity ratios for inhibiting the yeast over the human cytosolic CA isoforms. PMID:25669351

  12. Semicrystalline Polymers via Ring-Opening Polymerization: Preparation and Polymerization of Alkylene Phthalate Cyclic Oligomers.

    PubMed

    Brunelle; Bradt; Serth-Guzzo; Takekoshi; Evans; Pearce; Wilson

    1998-07-28

    Preparation of cyclic oligomeric alkylene phthalates via pseudo-high dilution condensation of alkylene diols with iso- and terephthaloyl chlorides and conversion to high molecular weight polyesters via ring-opening polymerization is described. Sterically unhindered amines such as quinuclidine or 1,4-diazabicyclo[2.2.2]octane (DABCO) catalyze the condensation significantly faster than other tertiary amines and are useful for carrying out this conversion in high yield, in the first direct reaction of diol and diacid chloride to form cyclic polyesters. The mixtures of oligomeric cyclics melt at 150-200 degrees C, providing liquids of low viscosity. Ring-opening polymerization using tin or titanate catalysts affords high molecular weight polymers within minutes. Complete polymerization of PBT oligomeric cyclics can be achieved at 180-200 degreesC, significantly below the polymer's melting point of 225 degreesC, and with molecular weights as high as 445 x 10(3). Polymers formed via such a process are more crystalline than conventionally prepared polyesters. PMID:9680414

  13. Laser desorption ionization of small molecules assisted by tungsten oxide and rhenium oxide particles.

    PubMed

    Bernier, Matthew C; Wysocki, Vicki H; Dagan, Shai

    2015-07-01

    Inorganic metal oxides have shown potential as matrices for assisting in laser desorption ionization with advantages over the aromatic acids typically used. Rhenium and tungsten oxides are attractive options due to their high work functions and relative chemical inertness. In this work, it is shown that ReO3 and WO3 , in microparticle (μP) powder forms, can efficiently facilitate ionization of various types of small molecules and provide minimized background contamination at analyte concentrations below 1 ng/µL. This study shows that untreated inorganic WO3 and ReO3 particles are valid matrix options for detection of protonatable, radical, and precharged species under laser desorption ionization. Qualitatively, the WO3 μP showed improved detection of apigenin, sodiated glucose, and precharged analyte choline, while the ReO3 μP allowed better detection of protonated cocaine, quinuclidine, ametryn, and radical ions of polyaromatic hydrocarbons at detection levels as low as 50 pg/µL. For thermometer ion survival yield experiments, it was also shown that the ReO3 powder was significantly softer than α-cyano-4-hydroxycinnaminic acid. Furthermore, it provided higher intensities of cocaine and polyaromatic hydrocarbons, at laser flux values equal to those used with α-cyano-4-hydroxycinnaminic acid. PMID:26349643

  14. Theoretical investigation on mechanism of asymmetric Michael addition of malononitrile to chalcones catalyzed by Cinchona alkaloid aluminium(III) complex.

    PubMed

    Su, Zhishan; Lee, Hai Whang; Kim, Chan Kyung

    2011-09-21

    The mechanism of Michael addition of malononitrile to chalcones catalyzed by Cinchona alkaloid aluminium(III) complex has been investigated by DFT and ONIOM methods. Calculations indicate that the reaction proceeds through a dual activation mechanism, in which Al(III) acts as a Lewis acid to activate the electrophile α,β-unsaturated carbonyl substrate while the tertiary amine in the Cinchona alkaloid works as a Lewis base to promote the activation of the malononitrile and deprotonation. A stepwise pathway involving C-C bond formation followed by proton transfer from the catalyst to the carbonyl substrate is adopted, and latter step is predicted to be the rate-determining-step in the reaction with an energy barrier of 12.4 kcal mol(-1). In the absence of the Al(III)-complex, a Cinchona alkaloid activates the carbonyl substrate by a hydrogen bonding of the hydroxyl group, involving a higher energy barrier of 30.4 kcal mol(-1). The steric repulsion between the phenyl group attached to the carbonyl group in the chalcone and isopropoxyl groups of the Al(III)-complex may play an important role in the control of stereoselectivity. The π-π stacking effect between the quinuclidine ring of the quinine and the phenyl group of the chalcones may also help the stabilization of the preferred molecular complex. These results are in agreement with experimental observations. PMID:21796318

  15. CYP450 phenotyping and metabolite identification of quinine by accurate mass UPLC-MS analysis: a possible metabolic link to blackwater fever

    PubMed Central

    2013-01-01

    Background The naturally occurring alkaloid drug, quinine is commonly used for the treatment of severe malaria. Despite centuries of use, its metabolism is still not fully understood, and may play a role in the haemolytic disorders associated with the drug. Methods Incubations of quinine with CYPs 1A2, 2C9, 2C19, 2D6, and 3A4 were conducted, and the metabolites were characterized by accurate mass UPLC-MSE analysis. Reactive oxygen species generation was also measured in human erythrocytes incubated in the presence of quinine with and without microsomes. Results The metabolites 3-hydroxyquinine, 2’-oxoquininone, and O-desmethylquinine were observed after incubation with CYPs 3A4 (3-hydroxyquinine and 2’-oxoquininone) and 2D6 (O-desmethylquinine). In addition, multiple hydroxylations were observed both on the quinoline core and the quinuclidine ring system. Of the five primary abundance CYPs tested, 3A4, 2D6, 2C9, and 2C19 all demonstrated activity toward quinine, while 1A2 did not. Further, quinine produced robust dose-dependent oxidative stress in human erythrocytes in the presence of microsomes. Conclusions Taken in context, these data suggest a CYP-mediated link between quinine metabolism and the poorly understood haemolytic condition known as blackwater fever, often associated with quinine ingestion. PMID:23800033

  16. Mechanism of phosphine borane deprotection with amines: the effects of phosphine, solvent and amine on rate and efficiency.

    PubMed

    Lloyd-Jones, Guy C; Taylor, Nicholas P

    2015-03-27

    The kinetics of borane transfer from simple tertiary phosphine borane adducts to a wide range of amines have been determined. All data obtained, including second-order kinetics, lack of cross-over, and negative entropies of activation for reaction of triphenylphosphine borane with quinuclidine and triethylamine, are consistent with a direct (SN 2-like) transfer process, rather than a dissociative (SN 1-like) process. The identities of the amine, phosphine, and solvent all impact substantially on the rate (k) and equilibrium (K) of the transfer, which in some cases vary by many orders of magnitude. P-to-N transfer is more efficient with cyclic amines in apolar solvents due to reduced entropic costs and ground-state destabilisation. Taken as a whole, the data allow informed optimisation of the deprotection step from the stand-point of rate, or synthetic convenience. In all cases, both reactants should be present at high initial concentration to gain kinetic benefit from the bimolecularity of the process. Ultimately, the choice of amine is dictated by the identity of the phosphine borane complex. Aryl-rich phosphine boranes are sufficiently reactive to allow use of diethylamine or pyrrolidine as a volatile low polarity solvent and reactant, whereas more alkyl-rich phosphines benefit from the use of more reactive amines, such as 1,4-diaza[2.2.2]bicyclooctane (DABCO), in apolar solvents at higher temperatures. PMID:25704230

  17. Laser Desorption Ionization of small molecules assisted by Tungsten oxide and Rhenium oxide particles

    PubMed Central

    Bernier, Matthew; Wysocki, Vicki; Dagan, Shai

    2015-01-01

    Inorganic metal oxides have shown potential as matrices for assisting in laser desorption ionization (LDI) with advantages over the aromatic acids typically used. Rhenium and tungsten oxides are an attractive option due to their high work functions and relative chemical inertness. In this work, it is shown that ReO3 and WO3, in microparticle (μP) powder forms, can efficiently ionize various types of small molecules and provide minimized background contamination at analyte concentrations below 1 ng/μL. This study shows that untreated inorganic WO3 and ReO3 particles are valid matrix options for detection of protonatable, radical, and precharged species under LDI. Qualitatively, the WO3 μP showed an improved detection of apigenin, sodiated glucose, and the precharged analyte choline, while the ReO3 μP allowed detection of protonated cocaine, quinuclidine, ametryn, and radical ions of polyaromatic hydrocarbons at detection levels as low as 50 pg/μL. For thermometer ion survival yield experiments, it was also shown that the ReO3 powder was significantly softer than CCA. Furthermore, it provided higher intensities of cocaine and polyaromatic hydrocarbons, at laser flux values equal to that used with CCA. PMID:26349643

  18. Investigation of the stability of the M-H-B bond in borane sigma complexes [M(CO)5(eta1-BH2R.L)] and [CpMn(CO)2(eta1-BH2R.L)] (M=Cr, W; L=tertiary amine or phosphine): substituent and Lewis base effects.

    PubMed

    Kawano, Yasuro; Yamaguchi, Kazunori; Miyake, Shun-ya; Kakizawa, Taeko; Shimoi, Mamoru

    2007-01-01

    We investigated the influence of a substituent and a Lewis base on boron upon the thermodynamic stability of metal complexes of borane-Lewis base adducts, [M(CO)5(eta1-BH(2)R.L)] (M=Cr, W) and [CpMn(CO)2(eta1-BH2R.L)], where R=Cl, I, m-C6H4F, Ph, H, Me, Et; L=PMe3, PPh3, NMe3, quinuclidine. In these compounds, the stability of the metal-borane linkage was enhanced by increasing the electron-releasing ability of the substituent on boron. A stronger base L additionally stabilized the complexes. The strength of the borane-metal interaction is thus mainly ascribed to the electron donation from the BH sigma orbital to metal rather than the back-donation into the BH sigma* orbital. This result supports the bonding model for the B-H-M linkage in the borane complexes suggested by MO calculations, where the borane-to-metal electron donation is predominant while the metal back-donation into the BH sigma* orbital is negligible. Such a stability trend of the borane complexes makes a sharp contrast to that of many silane and dihydrogen complexes. PMID:17525921

  19. Structure-affinity relationship of the cocaine-binding aptamer with quinine derivatives.

    PubMed

    Slavkovic, Sladjana; Altunisik, Merve; Reinstein, Oren; Johnson, Philip E

    2015-05-15

    In addition to binding its target molecule, cocaine, the cocaine-binding aptamer tightly binds the alkaloid quinine. In order to understand better how the cocaine-binding aptamer interacts with quinine we have used isothermal titration calorimetry-based binding experiments to study the interaction of the cocaine-binding aptamer to a series of structural analogs of quinine. As a basis for comparison we also investigated the binding of the cocaine-binding aptamer to a set of cocaine metabolites. The bicyclic aromatic ring on quinine is essential for tight affinity by the cocaine-binding aptamer with 6-methoxyquinoline alone being sufficient for tight binding while the aliphatic portion of quinine, quinuclidine, does not show detectable binding. Compounds with three fused aromatic rings are not bound by the aptamer. Having a methoxy group at the 6-position of the bicyclic ring is important for binding as substituting it with a hydrogen, an alcohol or an amino group all result in lower binding affinity. For all ligands that bind, association is driven by a negative enthalpy compensated by unfavorable binding entropy. PMID:25858454

  20. Designing the synthesis of catalytically active Ti-β by using various new templates in the presence of fluoride anion.

    PubMed

    Sasidharan, Manickam; Bhaumik, Asim

    2011-09-28

    Crystallization of large-pore Ti-β by using a variety of diquaternary ammonium derivatives of dibromoalkane and amines such as triethylamine, 1,4-diazabicyclo[2,2,2]octane (DABCO), and quinuclidine as structure-directing agents (SDA) is described. The size of hydrophobic bridging alkyl-chain length of the template [R(3)N(+)-(CH(2))(x)-N(+)R(3)](OH(-))(2) directs the final crystalline product: Ti-β, Ti-ZSM-12, Ti-nonasil or Ti-ZSM-5, as x gradually changes from 6 to 1, in the fluoride medium under hydrothermal conditions. A dense phase such as Ti-nonasil (clathrasil type) is crystallized as the size of hydrophobic bridging alkyl-chain length decreases. The use of F(-) anions as a mineralizer and Ti(4+) as a heteroatom in the synthesis gel also influences the selectivity of final crystalline product. The phase purity and incorporation of Ti(4+) into the lattice of β (BEA) and ZSM-12 frameworks are confirmed using XRD, UV-visible, FT-IR, (29)Si NMR spectroscopes, elemental analysis (ICP), surface area measurements and catalytic test reactions. The morphology of Ti-β samples is dependent on the nature of the structure-directing agent as revealed by the scanning electron microscopic (SEM) observations. The catalytic activity in the epoxidation of 4-vinyl-1-cyclohexene is increased with the amount of tetrahedral Ti(4+) atoms in the framework. The new templates can be effectively used for preparation of catalytically active Ti-β with the minimum number of framework defect sites. PMID:21833381

  1. In vivo protection against soman toxicity by known inhibitors of acetylcholine synthesis in vitro.

    PubMed

    Sterling, G H; Doukas, P H; Sheldon, R J; O'Neill, J J

    1988-02-01

    Soman inhibits the enzyme acetylcholinesterase, essentially irreversibly, producing an accumulation of acetylcholine (ACh) which is responsible for many of its toxic effects. Current approaches to treatment include: (1) atropine, a muscarinic receptor blocker; (2) pyridine-2-aldoxime methylchloride (2-PAM), an enzyme reactivator; and (3) carbamate protection of the enzyme. However, no fully satisfactory regimen has been found, primarily because of the rapid aging process. In this study, compounds known to inhibit ACh synthesis in vitro were evaluated in combination with atropine and 2-PAM so as to assess their potential utility in protection against soman toxicity in rats. Acetylsecohemicholinium (100 micrograms/kg, i.c.v.t., 30 min prior to soman), an inhibitor of high affinity choline uptake (HAChU) and cholineacetyltransferase (ChAT) activity in vitro, enhanced the protective effects of atropine and 2-PAM, reducing the mortality within the first 2 hr following soman. N-Hydroxyethylnaphthylvinylpyridine (NHENVP), a quaternary ChAT inhibitor (1.7 mumol/kg, i.m.), significantly reduced the overall percent mortality due to soman from 80% to 20%. The compound was most effective when administered 2-3 min prior to soman and was effective only by the intramuscular route. N-Allyl-3-quinuclidinol, a potent HAChU inhibitor (1 mumol/kg, i.m.) was the most effective quinuclidine analog evaluated, also reducing the percent mortality for a 24-hr period. Unlike NHENVP, it was most effective when given 30-60 min prior to soman. It is suggested from the data that compounds that disrupt presynaptic ACh synthesis in vitro may prove effective in treating organophosphate poisoning. The results demonstrate interesting differences among the compounds studied and provide insight for the design of protectants against soman toxicity. These findings further underscore the need to examine the structure activity and pharmacokinetic properties of these compounds, i.e. comparison of routes of

  2. Synthetic arylquinuclidine derivatives exhibit antifungal activity against Candida albicans, Candida tropicalis and Candida parapsilopsis

    PubMed Central

    2011-01-01

    Background Sterol biosynthesis is an essential pathway for fungal survival, and is the biochemical target of many antifungal agents. The antifungal drugs most widely used to treated fungal infections are compounds that inhibit cytochrome P450-dependent C14α-demethylase (CYP51), but other enzymes of this pathway, such as squalene synthase (SQS) which catalyses the first committed step in sterol biosynthesis, could be viable targets. The aim of this study was to evaluate the antifungal activity of SQS inhibitors on Candida albicans, Candida tropicalis and Candida parapsilopsis strains. Methods Ten arylquinuclidines that act as SQS inhibitors were tested as antiproliferative agents against three ATCC strains and 54 clinical isolates of Candida albicans, Candida tropicalis and Candida parapsilopsis. Also, the morphological alterations induced in the yeasts by the experimental compounds were evaluated by fluorescence and transmission electron microscopy. Results The most potent arylquinuclidine derivative (3-[1'-{4'-(benzyloxy)-phenyl}]-quinuclidine-2-ene) (WSP1267) had a MIC50 of 2 μg/ml for all species tested and MIC90 varying from 4 μg/ml to 8 μg/ml. Ultrathin sections of C. albicans treated with 1 μg/ml of WSP1267 showed several ultrastructural alterations, including (a) loss of cell wall integrity, (b) detachment of the plasma membrane from the fungal cell wall, (c) accumulation of small vesicles in the periplasmic region, (d) presence of large electron-dense vacuoles and (e) significantly increased cell size and cell wall thickness. In addition, fluorescence microscopy of cells labelled with Nile Red showed an accumulation of lipid droplets in the cytoplasm of treated yeasts. Nuclear staining with DAPI revealed the appearance of uncommon yeast buds without a nucleus or with two nuclei. Conclusion Taken together, our data demonstrate that arylquinuclidine derivatives could be useful as lead compounds for the rational synthesis of new antifungal drugs. PMID

  3. Squalene synthase inhibitors: An update on the search for new antihyperlipidemic and antiatherosclerotic agents.

    PubMed

    Kourounakis, A P; Katselou, M G; Matralis, A N; Ladopoulou, E M; Bavavea, E

    2011-01-01

    Atherosclerosis and related heart disease is strongly associated with elevated blood levels of total (and LDL) cholesterol. Due to the widespread incidence as well as severity of this pathological condition, major efforts have been made for the discovery and development of hypocholesteroleamic agents. In the past few decades, HMG-CoA reductase inhibitors (statins) are being extensively used as lipid lowering drugs. These agents act predominantly by inhibiting the enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) that is the rate limiting step of cholesterol biosynthesis. Both the success as well as drawbacks of HMGRIs, have led to the investigation and design of inhibitors of other (downstream) enzymes involved in the multistep cholesterol biosynthetic pathway. One such class of agents consists of the squalene sythase inhibitors which act at the first and solely committed step towards the biosynthesis of the cholesterol nucleus. This target is considered not to interfere with the biosynthesis of other biologically important molecules and thus a better side-effect profile is expected for these inhibitors. Several classes of squalene synthase inhibitors (SQSIs), such as substrate or transition-state analogues, zaragozic acids or 2,8- dioxabicyclo[3.2.1]octane derivatives, dicarboxylic acid and quinuclidine derivatives, 4,1-benzoxazepine as well as substituted morpholine derivatives, have been studied as potent inhibitors of squalene synthase. So far only one benzoxazepine derivative (TAK-475) has been evaluated in advanced clinical trials. In this article we review the up to date research and literature on the therapeutic potential of this relatively new class of compounds, the drug discovery efforts towards the development of active squalene synthase inhibitors, their activity profile and effectiveness, as well as their structure-activity relationships. PMID:21864285

  4. Mixed-mode ion-exchangers and their comparative chromatographic characterization in reversed-phase and hydrophilic interaction chromatography elution modes.

    PubMed

    Lämmerhofer, Michael; Richter, Martin; Wu, Junyan; Nogueira, Raquel; Bicker, Wolfgang; Lindner, Wolfgang

    2008-08-01

    A set of particulate silica-supported mixed-mode RP/weak anion-exchangers (RP/WAX) (obtained by bonding of N-undecenoylated 3-aminoquinuclidine, 3-aminotropane and 2-dimethylaminoethylamine as well as of N-butenoyl-(2S,4S,5R)-2-aminomethyl-5-[(2-octylthio)ethyl]-quinuclidine to thiol-modified silica) were chromatographically characterized in comparison to selected commercially available columns using two distinct isocratic elution modes, viz. an aqueous-rich RP-type elution mode (with 40% ACN and 60% buffer) as well as an organic solvent-rich hydrophilic interaction chromatography (HILIC)-type elution mode (95 and 90% ACN). The mixed-mode RP/WAX phases showed multimodal applicability, unlike a polar embedded RP material (Synergi Fusion RP), amino phases (Luna NH(2), BioBasic AX) or typical HILIC packings (ZIC-HILIC, TSKGel Amide-80). Principal component analysis (PCA) of the RP test data confirmed that the in-house developed RP/WAX columns as well as the Acclaim Mixed-Mode WAX-1 phase resemble each other in their chromatographic characteristics having slightly lower hydrophobic selectivity (alpha(CH2) of 1.5) than the tested Synergi Fusion RP (alpha(CH2) approximately 1.8). In contrast, a decrease in mixed-mode character due to lowered ion-exchange capacity and concomitantly increased RP-like behavior could be identified for other mixed-mode phases in the order of Obelisc R > Primesep B2 > Uptisphere MM3. PCA on HILIC data revealed that the RP/WAX phases behave dissimilar to TSKGel Amide-80, ZIC-HILIC and polysulfoethyl A under the chosen elution conditions. Hence, they may be regarded as complementary to these commercial stationary phases with applicability profiles for hydrophilic but also hydrophobic solutes. PMID:18693304

  5. Docking studies of benzylidene anabaseine interactions with α7 nicotinic acetylcholine receptor (nAChR) and acetylcholine binding proteins (AChBPs): Application to the design of related α7 selective ligands

    PubMed Central

    Kombo, David C.; Mazurov, Anatoly; Tallapragada, Kartik; Hammond, Philip S.; Chewning, Joseph; Hauser, Terry A.; Vasquez-Valdivieso, Montserrat; Yohannes, Daniel; Talley, Todd T.; Taylor, Palmer; Caldwell, William S.

    2016-01-01

    AChBPs isolated from Lymnaea stagnalis (Ls), Aplysia californica (Ac) and Bulinus truncatus (Bt) have been extensively used as structural prototypes to understand the molecular mechanisms that underlie ligand-interactions with nAChRs [1]. Here, we describe docking studies on interactions of benzylidene anabaseine analogs with AChBPs and α7 nAChR. Results reveal that docking of these compounds using Glide software accurately reproduces experimentally-observed binding modes of DMXBA and of its active metabolite, in the binding pocket of Ac. In addition to the well-known nicotinic pharmacophore (positive charge, hydrogen-bond acceptor, and hydrophobic aromatic groups), a hydrogen-bond donor feature contributes to binding of these compounds to Ac, Bt, and the α7 nAChR. This is consistent with benzylidene anabaseine analogs with OH and NH2 functional groups showing the highest binding affinity of these congeners, and the position of the ligand shown in previous X-ray crystallographic studies of ligand-Ac complexes. In the predicted ligand-Ls complex, by contrast, the ligand OH group acts as hydrogen-bond acceptor. We have applied our structural findings to optimizing the design of novel spirodiazepine and spiroimidazoline quinuclidine series. Binding and functional studies revealed that these hydrogen-bond donor containing compounds exhibit improved affinity and selectivity for the α7 nAChR subtype and demonstrate partial agonism. The gain in affinity is also due to conformational restriction, tighter hydrophobic enclosures, and stronger cation-π interactions. The use of AChBPs structure as a surrogate to predict binding affinity to α7 nAChR has also been investigated. On the whole, we found that molecular docking into Ls binding site generally scores better than when a α7 homology model, Bt or Ac crystal structure is used. PMID:21986237

  6. Cognitive improvements in a mouse model with substituted 1,2,3-triazole agonists for nicotinic acetylcholine receptors.

    PubMed

    Arunrungvichian, Kuntarat; Boonyarat, Chantana; Fokin, Valery V; Taylor, Palmer; Vajragupta, Opa

    2015-08-19

    The α7 nicotinic acetylcholine receptor (nAChR) is a recognized drug target for dementias of aging and certain developmental disorders. Two selective and potent α7-nAChR agonists, winnowed from a list of 43 compounds characterized in a companion article (DOI: 10.1021/acschemneuro.5b00058), 5-((quinuclid-3-yl)-1H-1,2,3-triazol-4-yl)-1H-indole (IND8) and 3-(4-hydroxyphenyl-1,2,3-triazol-1-yl) quinuclidine (QND8), were evaluated for cognitive improvement in both short- and long-term memory. Tacrine, a centrally active acetylcholinesterase inhibitor, and PNU-282987, a congeneric α7 nAChR agonist, were employed as reference standards. Three behavioral tests, modified Y-maze, object recognition test (ORT), and water maze, were performed in scopolamine-induced amnesic mice. Intraperitoneal injection of these two compounds significantly improved the cognitive impairment in a modified Y-maze test (5 μmol/kg for IND8 and 10 μmol/kg for QND8), ORT (10 μmol/kg), and water maze test (25 μmol/kg). For delay induced memory deficit or natural memory loss in mice, IND8 and QND8 at 10 μmol/kg were able to enhance memory comparable to PNU-282987 when evaluated using ORT time delay model. Cognitive enhancement of IND8 and QND8 was mediated through α7-nAChRs as evidenced by its complete abolition after pretreatment with a selective α7-nAChR antagonist, methyllycaconitine. These data demonstrate that IND8 and QND8 and their congeners are potential candidates for treatment of cognitive disorders, and the substituted triazole series formed by cycloaddition of alkynes and azides warrant further preclinical optimization. PMID:25978789

  7. Solvent isotope effects on nucleophilic displacement reactions

    SciTech Connect

    Spiegel, G.W.

    1981-01-01

    The kinetic solvent isotope effect, KSIE, (k/sub H/sub 2/O//k/sub D/sub 2/O/), at 25.0/sup 0/C and ionic strength, I, equal to 0.20 +- 0.02 M was measured for the nucleophilic displacement of iodine ion from iodomethane, iodoacetamide, and iodoacetate ion, thiophene from S-Methylthiophenium ion, and tosylate ion from methyl tosylate by bromide ion, chloride ion, acetate ion, hydroxide ion, water, ammonia, ethylenediamine, n-butylamine, piperazine, piperidine, quinuclidine, and 1,4-Diazabicyclo(2.2.2)octane (DABCO), and the monoprotonated cations of ethylenediamine, piperazine, and DABCO. By means of solvent partition measurements at 25.0/sup 0/C and I = 0.02 M between H/sub 2/O and D/sub 2/O and a common immiscible organic solvent, the ground state activity coefficients in D/sub 2/O, the solution in H/sub 2/O being chosen as the reference state, were determined for the nitrogen-containing nucleophiles (except ammonia) and the substrates methyl tosylate, iodoacetamide, and iodoacetic acid. The solubilities at 25.0/sup 0/C of the picrate and tetraphenylborate salts of the monoprotonated cationic forms of ethylenediamine, piperazine, and DABCO were measured to determine the activity coefficients in D/sub 2/O of these ions relative to an H/sub 2/O reference state. Applying the Eyring equation, the activity coefficients of the transition states in D/sub 2/O, reference state H/sub 2/O, were calculated.

  8. Enantioselective hydrogenation. III. Methyl pyruvate hydrogenation catalyzed by alkaloid-modified iridium

    SciTech Connect

    Simons, K.E.; Johnston, P.; Plum, H.; Wells, P.B.; Ibbotson, A.

    1994-12-01

    Enantioselective hydrogenation of methyl pyruvate, MeCOCOOMe to methyl lactate, MeCH(OH)COOMe, is catalyzed in solution at room temperature by supported iridium catalysts modified with cinchona alkaloids. Modification with cinchonidine or quinine yields R-lactate in excess, whereas modification with cinchonine or quinidine favors S-lactate formation. Ir/SiO{sub 2} catalysts (20%) calcined at 393 to 573 K and reduced at 523 to 593 K were highly active for racemic hydrogenation in the absence of a modifier (rates typically 1.8 mol h{sup -1} g{sub cat}{sup -1}) and were comparably active when modified with cinchonidine but gave an enantiomeric excess of about 30%. Use of higher calcination or reduction temperatures led to substantially inferior activity and selectivity. The high rates recorded for both racemic and enantioselective reactions are dependent on the catalysts being activated before use by a procedure involving exposure of the catalyst to air after the initial reduction. Use of a Cl-free precursor gave an Ir/SiO{sub 2} catalyst (20%) of superior activity but inferior enantioselectivity. Ir/CaCO{sub 3} (5%) was more active for racemic hydrogenation than for enantioselective hydrogenation, but provided the highest value of the enantiomeric excess 39%. Kinematics of reaction are reported. Exchange of H for D in 10,11-dihydrocinchonidine at room temperature over Ir/CaCO{sub 3} occurred in the quinoline moiety but not in the quinuclidine ring system, indicating that the alkaloid was adsorbed to the Ir surface via the interaction of its {pi}-electron system. For both silica-supported and calcium carbonate-supported Ir, the presence of chloride ion in the catalyst was advantageous for the achievement of enantioselectivity. 25 refs., 2 figs., 3 tabs.

  9. Potent In Vitro Antiproliferative Synergism of Combinations of Ergosterol Biosynthesis Inhibitors against Leishmania amazonensis

    PubMed Central

    de Macedo-Silva, S. T.; Visbal, G.; Urbina, J. A.; de Souza, W.

    2015-01-01

    Leishmaniases comprise a spectrum of diseases caused by protozoan parasites of the Leishmania genus. Treatments available have limited safety and efficacy, high costs, and difficult administration. Thus, there is an urgent need for safer and more-effective therapies. Most trypanosomatids have an essential requirement for ergosterol and other 24-alkyl sterols, which are absent in mammalian cells. In previous studies, we showed that Leishmania amazonensis is highly susceptible to aryl-quinuclidines, such as E5700, which inhibit squalene synthase, and to the azoles itraconazole (ITZ) and posaconazole (POSA), which inhibit C-14α-demethylase. Herein, we investigated the antiproliferative, ultrastructural, and biochemical effects of combinations of E5700 with ITZ and POSA against L. amazonensis. Potent synergistic antiproliferative effects were observed against promastigotes, with fractional inhibitory concentration (FIC) ratios of 0.0525 and 0.0162 for combinations of E5700 plus ITZ and of E5700 plus POSA, respectively. Against intracellular amastigotes, FIC values were 0.175 and 0.1125 for combinations of E5700 plus ITZ and E5700 plus POSA, respectively. Marked alterations of the ultrastructure of promastigotes treated with the combinations were observed, in particular mitochondrial swelling, which was consistent with a reduction of the mitochondrial transmembrane potential, and an increase in the production of reactive oxygen species. We also observed the presence of vacuoles similar to autophagosomes in close association with mitochondria and an increase in the number of lipid bodies. Both growth arrest and ultrastructural/biochemical alterations were strictly associated with the depletion of the 14-desmethyl endogenous sterol pool. These results suggest the possibility of a novel combination therapy for the treatment of leishmaniasis. PMID:26239973

  10. Potent In Vitro Antiproliferative Synergism of Combinations of Ergosterol Biosynthesis Inhibitors against Leishmania amazonensis.

    PubMed

    de Macedo-Silva, S T; Visbal, G; Urbina, J A; de Souza, W; Rodrigues, J C F

    2015-10-01

    Leishmaniases comprise a spectrum of diseases caused by protozoan parasites of the Leishmania genus. Treatments available have limited safety and efficacy, high costs, and difficult administration. Thus, there is an urgent need for safer and more-effective therapies. Most trypanosomatids have an essential requirement for ergosterol and other 24-alkyl sterols, which are absent in mammalian cells. In previous studies, we showed that Leishmania amazonensis is highly susceptible to aryl-quinuclidines, such as E5700, which inhibit squalene synthase, and to the azoles itraconazole (ITZ) and posaconazole (POSA), which inhibit C-14α-demethylase. Herein, we investigated the antiproliferative, ultrastructural, and biochemical effects of combinations of E5700 with ITZ and POSA against L. amazonensis. Potent synergistic antiproliferative effects were observed against promastigotes, with fractional inhibitory concentration (FIC) ratios of 0.0525 and 0.0162 for combinations of E5700 plus ITZ and of E5700 plus POSA, respectively. Against intracellular amastigotes, FIC values were 0.175 and 0.1125 for combinations of E5700 plus ITZ and E5700 plus POSA, respectively. Marked alterations of the ultrastructure of promastigotes treated with the combinations were observed, in particular mitochondrial swelling, which was consistent with a reduction of the mitochondrial transmembrane potential, and an increase in the production of reactive oxygen species. We also observed the presence of vacuoles similar to autophagosomes in close association with mitochondria and an increase in the number of lipid bodies. Both growth arrest and ultrastructural/biochemical alterations were strictly associated with the depletion of the 14-desmethyl endogenous sterol pool. These results suggest the possibility of a novel combination therapy for the treatment of leishmaniasis. PMID:26239973

  11. Sterol Biosynthesis Pathway as Target for Anti-trypanosomatid Drugs

    PubMed Central

    de Souza, Wanderley; Rodrigues, Juliany Cola Fernandes

    2009-01-01

    Sterols are constituents of the cellular membranes that are essential for their normal structure and function. In mammalian cells, cholesterol is the main sterol found in the various membranes. However, other sterols predominate in eukaryotic microorganisms such as fungi and protozoa. It is now well established that an important metabolic pathway in fungi and in members of the Trypanosomatidae family is one that produces a special class of sterols, including ergosterol, and other 24-methyl sterols, which are required for parasitic growth and viability, but are absent from mammalian host cells. Currently, there are several drugs that interfere with sterol biosynthesis (SB) that are in use to treat diseases such as high cholesterol in humans and fungal infections. In this review, we analyze the effects of drugs such as (a) statins, which act on the mevalonate pathway by inhibiting HMG-CoA reductase, (b) bisphosphonates, which interfere with the isoprenoid pathway in the step catalyzed by farnesyl diphosphate synthase, (c) zaragozic acids and quinuclidines, inhibitors of squalene synthase (SQS), which catalyzes the first committed step in sterol biosynthesis, (d) allylamines, inhibitors of squalene epoxidase, (e) azoles, which inhibit C14α-demethylase, and (f) azasterols, which inhibit Δ24(25)-sterol methyltransferase (SMT). Inhibition of this last step appears to have high selectivity for fungi and trypanosomatids, since this enzyme is not found in mammalian cells. We review here the IC50 values of these various inhibitors, their effects on the growth of trypanosomatids (both in axenic cultures and in cell cultures), and their effects on protozoan structural organization (as evaluted by light and electron microscopy) and lipid composition. The results show that the mitochondrial membrane as well as the membrane lining the protozoan cell body and flagellum are the main targets. Probably as a consequence of these primary effects, other important changes take place in

  12. Sterol Biosynthesis Pathway as Target for Anti-trypanosomatid Drugs.

    PubMed

    de Souza, Wanderley; Rodrigues, Juliany Cola Fernandes

    2009-01-01

    Sterols are constituents of the cellular membranes that are essential for their normal structure and function. In mammalian cells, cholesterol is the main sterol found in the various membranes. However, other sterols predominate in eukaryotic microorganisms such as fungi and protozoa. It is now well established that an important metabolic pathway in fungi and in members of the Trypanosomatidae family is one that produces a special class of sterols, including ergosterol, and other 24-methyl sterols, which are required for parasitic growth and viability, but are absent from mammalian host cells. Currently, there are several drugs that interfere with sterol biosynthesis (SB) that are in use to treat diseases such as high cholesterol in humans and fungal infections. In this review, we analyze the effects of drugs such as (a) statins, which act on the mevalonate pathway by inhibiting HMG-CoA reductase, (b) bisphosphonates, which interfere with the isoprenoid pathway in the step catalyzed by farnesyl diphosphate synthase, (c) zaragozic acids and quinuclidines, inhibitors of squalene synthase (SQS), which catalyzes the first committed step in sterol biosynthesis, (d) allylamines, inhibitors of squalene epoxidase, (e) azoles, which inhibit C14alpha-demethylase, and (f) azasterols, which inhibit Delta(24(25))-sterol methyltransferase (SMT). Inhibition of this last step appears to have high selectivity for fungi and trypanosomatids, since this enzyme is not found in mammalian cells. We review here the IC50 values of these various inhibitors, their effects on the growth of trypanosomatids (both in axenic cultures and in cell cultures), and their effects on protozoan structural organization (as evaluted by light and electron microscopy) and lipid composition. The results show that the mitochondrial membrane as well as the membrane lining the protozoan cell body and flagellum are the main targets. Probably as a consequence of these primary effects, other important changes take

  13. Asymmetric fluorocyclizations of alkenes.

    PubMed

    Wolstenhulme, Jamie R; Gouverneur, Véronique

    2014-12-16

    CONSPECTUS: The vicinal fluorofunctionalization of alkenes is an attractive transformation that converts feedstock olefins into valuable cyclic fluorinated molecules for application in the pharmaceutical, agrochemical, medical, and material sectors. The challenges associated with asymmetric fluorocyclizations induced by F(+) reagents are distinct from other types of halocyclizations. Processes initiated by the addition of an F(+) reagent onto an alkene do not involve the reversible formation of bridged fluoronium ions but generate acyclic β-fluorocationic intermediates. This mechanistic feature implies that fluorocyclizations are not stereospecific. A discontinuity exists between the importance of this class of fluorocyclization and the activation modes currently available to implement successful catalysis. Progress toward fluorocyclization has been achieved by investing in neutral and cationic [NF] reagent development. The body of work on asymmetric fluorination using chiral cationic [NF](+) reagents prepared by fluorine transfer from the dicationic [NF](2+) reagent Selectfluor to quinuclidines, inspired the development of asymmetric F(+)-induced fluorocyclizations catalyzed by cinchona alkaloids; for catalysis, the use of N-fluorobenzenesulfonimide, which is less reactive than Selectfluor, ensures that the achiral F(+) source remains unreactive toward the alkene. These organocatalyzed enantioselective fluorocyclizations can be applied to indoles to install the fluorine on a quaternary benzylic stereogenic carbon center and to afford fluorinated analogues of natural products featuring the hexahydropyrrolo[2,3-b]indole or the tetrahydro-2H-furo[2,3-b]indole skeleton. In an alternative approach, the poor solubility of dicationic Selectfluor bis(tetrafluoroborate) in nonpolar solvent was exploited with anionic phase transfer catalysis as the operating activation mode. Exchange of the tetrafluoroborate ions of Selectfluor with bulky lipophilic chiral anions (e