Discovery of potent and novel S-nitrosoglutathione reductase inhibitors devoid of cytochrome P450 activities (original) (raw)
Related papers
Bioorganic & Medicinal Chemistry Letters, 2011
a b s t r a c t S-Nitrosoglutathione reductase (GSNOR) is a member of the alcohol dehydrogenase family (ADH) that regulates the levels of S-nitrosothiols (SNOs) through catabolism of S-nitrosoglutathione (GSNO). GSNO and SNOs are implicated in the pathogenesis of many diseases including those in respiratory, cardiovascular, and gastrointestinal systems. The pyrrole based N6022 was recently identified as a potent, selective, reversible, and efficacious GSNOR inhibitor which is currently undergoing clinical development. We describe here the synthesis and structure-activity relationships (SAR) of novel pyrrole based analogues of N6022 focusing on scaffold modification and propionic acid replacement. We identified equally potent and novel GSNOR inhibitors having pyrrole regioisomers as scaffolds using a structure based approach.
Journal of undergraduate chemistry research, 2013
Cytochrome P450 enzymes are a superfamily of hemoproteins involved in the metabolism of endogenous and exogenous compounds including many drugs and environmental chemicals. In our previous research, we have determined that certain aryl and arylalkyl acetylenes act as inhibitors of these enzymes. Here we report a family of propargyl ethers containing a pyridine ring system. Five new compounds, 2,4-dimethyl-3-(prop-2-yn-1-yloxy)pyridine(I), 2,4-dimethyl-3-((prop-2-yn-1-yloxy) methyl)pyridine(II), 2,3-dimethyl-4-((prop-2-yn-1-yloxy)methyl)pyridine(III), 2-methyl-4-((prop-2-yn-1-yloxy)methyl)pyridine (IV), 2-methyl-4-(prop-2-yn-1-yloxy)pyridine (V) (Figure 1) have been synthesized and characterized.
1-cyano-2-methyl-3-({[2-(5-methyl-1H-imidazol-4-yl)ethyl]sulfanyl}methyl)guanidine (cimetidine) is a drug that helps in the reduction of stomach acidity, pepsin output reduction and promotion of ulcer healing. We carried out molecular docking for six analogous structurally diverse 1-cyano-2-methyl-3-({[2-(5-methyl-1H-imidazol-4-yl)ethyl]sulfanyl}methyl)guanidine (cimetidine) with cytochrome P450 1A2 using Patchdock and Firedock softwares. Extensive structure activity relationship studies was carried out with the substituted derivatives and compared with the non-substituted. These molecules were designed by substituting different chemical groups on position 17 of cimetidine. The scoring function (empirical binding free energy) was used to estimate the free binding energy of the protein-ligand complex. The binding energy of cimetidine was-30.96 kcal/mol. The free binding energies of COOH, COCH3, NO2, CF3 and CONH2 analogues were-33.12,-31.67,-34.67,-34.73 and-36.58 Kcal/mol respectively. All the monosubstituted analogues showed lower values than the non substituted cimetidine. These lower values indicate that they inhibit CYP450 functional activity. These results suggest that the new inhibitors may cause hepatotoxicity. Synthesis and pre-clinical studies of these monosubstituted derivatives with cytochrome P450 1A2 receptors is recommended in order to confirm their hepatotoxicity.
The MDR-involved human GSTA1-1, an important isoenzyme overexpressed in several tumors leading to chemotherapeutic-resistant tumour cells, has been targeted by 2,2 0-dihydroxybenzophenones and some of their carbonyl N-analogues, as its potential inhibitors. A structure-based library of the latter was built-up by a nucleophilic cleavage of suitably substituted xanthones to 2,2 0-dihydroxy-benzophenones (5–9) and subsequent formation of their N-derivatives (oximes 11–13 and N-acyl hydrazones 14–16). Screening against hGSTA1-1 led to benzophenones 6 and 8, and hydrazones 14 and 16, having the highest inhibition potency (IC 50 values in the range 0.18 ± 0.02 to 1.77 ± 0.10 lM). Enzyme inhibition kinetics, molecular modeling and docking studies showed that they interact primarily at the CDNB-binding catalytic site of the enzyme. In addition, the results from cytotoxicity studies with human colon adenocarci-noma cells showed low LC 50 values for benzophenone 6 and its N-acyl hydrazone analogue 14 (31.4 ± 0.4 lM and 87 ± 1.9 lM, respectively), in addition to the strong enzyme inhibition profile (IC 50(6) = 1,77 ± 0.10 lM; IC 50(14) = 0.33 ± 0.05 lM). These structures may serve as leads for the design of new potent mono-and bi-functional inhibitors and pro-drugs against human GTSs.
Advances in Design and Development of Inhibitors of Nitric Oxide Synthases
Nitric oxide synthase (NOS) is a dimeric enzyme that catalyses the production of nitric oxide (NO) in the human body. The nitric oxide has been identified as the most interesting and vital mediators for normal and pathological processes, including the regulation of blood pressure, neurotransmission, and macrophage defence system, but the over production of it can be toxic, hence their inhibitors are desired. In this article, the various isoforms of NOS and their roles are described and a detail of the development of their inhibitors has been presented. The inhibitors studied include aminopyridines, iminopiperidines, N-phenylamidines, benzoxazolones, isothioureas, oxazepanes, thiazepanes, diazepanes, 4,5-disubstituted-1,3-oxazolidin-2-imine derivatives, thiazolidines, pyrazoles, pyrazolines, and some others
Journal of Medicinal Chemistry, 2009
Several analogs of gigantol (1) were synthesized to evaluate their effect on the complexes Ca 2þ ecalmodulin (CaM) and Ca 2þ eCaMeCaM sensitive phosphodiesterase 1 (PDE1). The compounds belong to four structural groups including, 1,2-diphenylethanes (2e11), diphenylmethanes (13e15), 1,3-diphenylpropenones (16e18), and 1,3-diphenylpropanes (20e22). In vitro enzymatic studies showed that all compounds except 11 inhibited the complex Ca 2þ eCaMePDE1 with IC 50 values ranging from 9 to 146 mM. On the other hand, all analogs but 11, 12 and 15 quenched the extrinsic fluorescence of the CaM biosensor hCaMeM124CemBBr to different extent, then revealing different affinities to CaM; their affinity constants (K m ) values were in the range of 3e80 mM. Molecular modeling studies indicated that all these compounds bound to CaM at the same site that the classical inhibitors trifluoperazine (TFP) and chlorpromazine (CPZ). Some of these analogs could be worthy candidates for developing new anti-tumor, local anesthetics, antidepressants, antipsychotic, or smooth muscle relaxant drugs, with anti-CaM properties due to their good affinity to CaM and the straightforwardness of their synthesis. In addition they could be valuable tools for the study of Ca 2þ eCaM functions.
Design, synthesis, and evaluation of potential inhibitors of nitric oxide synthase
Bioorganic & Medicinal Chemistry, 2008
Selective inhibitors of neuronal nitric oxide synthase (nNOS) were shown to protect brain and may be useful in the treatment of neurodegenerative diseases. In this context, our purpose has been to design and synthesize a new family of derivatives of thiadiazoles as possible inhibitors of nNOS. To achieve it a supervised artificial neural network model has been developed for the prediction of inhibition of Nitric Oxide Synthase using a dataset of 119 nNOS inhibitors. The definition of the molecules was achieved from a not-supervised neural network using a home made program named CODES. Also, thiadiazole-based heterocycles, previously predicted, were prepared as conformationally restricted analogues of a selective nNOS inhibitor, S-ethyl N-phenylisothiourea.
Bioorganic & Medicinal Chemistry, 2008
Nitric oxide (NO) prodrugs such as O 2 -(2,4-dinitrophenyl) 1-[(4-ethoxycarbonyl)piperazin-1-yl] diazen-1-ium-1,2-diolate (JS-K) are a growing class of promising NO-based therapeutics. Nitric oxide release from the anti-cancer lead compound, JS-K, is proposed to occur through a nucleophilic aromatic substitution by glutathione (GSH) catalyzed by glutathione S-transferase (GST) to form a diazeniumdiolate anion that spontaneously releases NO. In this study, a number of structural analogues of JS-K were synthesized and their chemical and biological properties were compared with those of JS-K. The homopiperazine analogue of JS-K showed anti-cancer activity that is comparable with that of JS-K but with a diminished reactivity towards both GSH and GSH/GST; both the aforementioned compounds displayed no cytotoxic activity towards normal renal epithelial cell line at concentrations where they significantly diminished the proliferation of a panel of renal cancer cell lines. These properties may prove advantageous in the further development of this class of nitric oxide prodrugs as cancer therapeutic agents.
Bioorganic & Medicinal Chemistry Letters, 2012
8-Acetyl-7-hydroxy-4-phenyl-2H-benzopyran-2-one as starting material a number of 8-substituted derivatives (i.e., hydrazones 2a,b, imine 2c, chalcones 3, pyrazoles 4, 3-cyano-2-oxo-dihydropyridines 5, and/or 3-cyano-2-imino-dihydropyridines 6) were synthesized and assayed for their anti-inflammatory, analgesic and antipyretic activities. Compounds 3c, 4b and 4i showed significant anti-inflammatory, analgesic and antipyretic activities. In addition, 1, 3b, 4d, 4e, 5b, 6a, 6c, 6d, 6e showed anti-inflammatory activity, 2b, 4h, 5e exhibit analgesic activity, and 2b, 4h, 5e showed antipyretic effect. In addition, molecular modeling and docking of the tested compounds into cyclooxygenase II complexed with its bound inhibitor indomethacin (4COX) using MOLSOFT ICM 3.4-8C program was performed in order to predict the affinity and orientation of the synthesized compounds at the active site. Also, it was found that the active compounds 1, 4i, 6a-e interact with both Serine 530, and Tyrosine 385 amino acids which are the main amino acids involved in the mechanism of cyclooxygenase II inhibition. The synthesis of the pyrazole-containing new compounds 4 proved a successful hit; also, the 2-imino derivatives of 3-cyano-dihydropyridines were more successful than the 2-oxo derivatives. According to these results, we can conclude that compounds 1, 3c, 4b, 4i, and 6c appear to be the most interesting and seem potentially attractive as anti-inflammatory, analgesic, and antipyretic agents.
Brazilian Journal of Pharmaceutical Sciences, 2015
A series of N-substituted 2-{[5-(1H-indol-3-ylmethyl)-1,3,4-oxadiazol-2-yl]sulfanyl}acetamides (8a-w) was synthesized in three steps. The first step involved the sequential conversion of 2-(1H-indol-3-yl)acetic acid (1) to ester (2) followed by hydrazide (3) formation and finally cyclization in the presence of CS2 and alcoholic KOH yielded 5-(1H-indole-3-yl-methyl)-1,3,4-oxadiazole-2-thiol (4). In the second step, aryl/aralkyl amines (5a-w) were reacted with 2-bromoacetyl bromide (6) in basic medium to yield 2-bromo-N-substituted acetamides (7a-w). In the third step, these electrophiles (7a-w) were reacted with 4 to afford the target compounds (8a-w). Structural elucidation of all the synthesized derivatives was done by 1H-NMR, IR and EI-MS spectral techniques. Moreover, they were screened for antibacterial and hemolytic activity. Enzyme inhibition activity was well supported by molecular docking results, for example, compound 8q exhibited better inhibitory potential against α-gluco...