Pyrimidine-based pyrazoles as cyclin-dependent kinase 2 inhibitors: Design, synthesis, and biological evaluation.

A series of new pyrimidine-pyrazole hybrid molecules were designed as inhibitors of cyclin-dependent kinase 2. Designed compounds were docked using Glide and the compounds showing good score values and encouraging interactions with the residues were selected for synthesis. They were then evaluated using CDK2-CyclinA2 enzyme inhibition by a luminescent ADP detection assay. We show that of the 26 compounds synthesized and evaluated, at least 5 compounds were found to be highly potent (IC50  < 20 nm); which can be further optimized to have selectivity over other kinase isoforms.

Explicit treatment of active-site waters enhances quantum mechanical/implicit solvent scoring: Inhibition of CDK2 by new pyrazolo[1,5-a]pyrimidines.

We present comprehensive testing of solvent representation in quantum mechanics (QM)-based scoring of protein-ligand affinities. To this aim, we prepared 21 new inhibitors of cyclin-dependent kinase 2 (CDK2) with the pyrazolo[1,5-a]pyrimidine core, whose activities spanned three orders of magnitude. The crystal structure of a potent inhibitor bound to the active CDK2/cyclin A complex revealed that the biphenyl substituent at position 5 of the pyrazolo[1,5-a]pyrimidine scaffold was located in a previously unexplored pocket and that six water molecules resided in the active site. Using molecular dynamics, protein-ligand interactions and active-site water H-bond networks as well as thermodynamics were probed. Thereafter, all the inhibitors were scored by the QM approach utilizing the COSMO implicit solvent model. Such a standard treatment failed to produce a correlation with the experiment (R2 = 0.49). However, the addition of the active-site waters resulted in significant improvement (R2 = 0.68). The activities of the compounds could thus be interpreted by taking into account their specific noncovalent interactions with CDK2 and the active-site waters. In summary, using a combination of several experimental and theoretical approaches we demonstrate that the inclusion of explicit solvent effects enhance QM/COSMO scoring to produce a reliable structure-activity relationship with physical insights. More generally, this approach is envisioned to contribute to increased accuracy of the computational design of novel inhibitors.

Thiazole: A Review on Chemistry, Synthesis and Therapeutic Importance of its Derivatives.

Thiazole, a unique heterocycle containing sulphur and nitrogen atoms, occupies an important place in medicinal chemistry. It is an essential core scaffold present in many natural (Vitamin B1- Thiamine) and synthetic medicinally important compounds. The versatility of thiazole nucleus demonstrated by the fact that it is an essential part of penicillin nucleus and some of its derivatives which have shown antimicrobial (sulfazole), antiretroviral (ritonavir), antifungal (abafungin), antihistaminic and antithyroid activities. The synthetic importance of thiazole derivatives, its reduced forms and condensed derivatives have been increased much by their recent applications as anticancer (tiazofurin), anthelmintic, vulcanising accelerators (mercaptobenzothiazole) and photographic sensitizers. Thiazole chemistry has developed steadily after the pioneering work of Hofmann and Hantsch. Bogert and co-workers made significant contribution to expand this field. Mills established the importance of thiazole ring in cyanine dyes which is used as photographic sensitizer. Benzothiazole, a fused derivative of thiazole have also proved its commercial value. Present review describes chemical and biological importance of thiazole and its condensed derivatives with an emphasis on recent developments.

Quantum mechanics-based scoring rationalizes the irreversible inactivation of parasitic Schistosoma mansoni cysteine peptidase by vinyl sulfone inhibitors.

The quantum mechanics (QM)-based scoring function that we previously developed for the description of noncovalent binding in protein-ligand complexes has been modified and extended to treat covalent binding of inhibitory ligands. The enhancements are (i) the description of the covalent bond breakage and formation using hybrid QM/semiempirical QM (QM/SQM) restrained optimizations and (ii) the addition of the new ΔG(cov)' term to the noncovalent score, describing the "free" energy difference between the covalent and noncovalent complexes. This enhanced QM-based scoring function is applied to a series of 20 vinyl sulfone-based inhibitory compounds inactivating the cysteine peptidase cathepsin B1 of the Schistosoma mansoni parasite (SmCB1). The available X-ray structure of the SmCB1 in complex with a potent vinyl sulfone inhibitor K11017 is used as a template to build the other covalently bound complexes and to model the derived noncovalent complexes. We present the correlation of the covalent score and its constituents with the experimental binding data. Four outliers are identified. They contain bulky R1' substituents structurally divergent from the template, which might induce larger protein rearrangements than could be accurately modeled. In summary, we propose a new computational approach and an optimal protocol for the rapid evaluation and prospective design of covalent inhibitors with a conserved binding mode.

Molecular docking study, green synthesis and pharmacological evaluation of 1,3,4-thiadiazole derivatives as potential antiepileptic agents.

Epilepsy is one of the commonly occurring chronic neurological disorders which involves abnormal electrical impulses in the brain. It is characterized by the sudden loss of consciousness, followed by abnormal shaking of the body. Though there are various types of antiepileptic drugs available clinically, the treatment of epilepsy still remains inadequate because of their toxicity and idiosyncratic side effects. Thus, there is unmet medical need to develop safe drugs for the treatment of epilepsy with lower side effects and improved bioavailability profiles. Considering the structural similarity between phenytoin/lamotrigine, a series of 1,3,4-thiadiazole was designed based on molecular docking study into the active site of the voltage-gated sodium channels. Antiepileptic activity of the synthesized compounds was evaluated in rats by maximal electroshock induced seizures (MES) model at different doses. Among the tested compounds, some exhibited significant anticonvulsant activity as compared to phenytoin in a dose-dependent manner. The neurotoxicity study was carried out using the rotarod test and the results of which suggests that the target compounds are safe and could be further developed as potential lead for antiepileptic drugs.

A rational approach to identify inhibitors of Mycobacterium tuberculosis enoyl acyl carrier protein reductase.

Mycobacterial enoyl acyl carrier protein (ACP) reductase is an attractive target for focused design of novel antitubercular agents. Structural information available on enoyl-ACP reductase in complex with different ligands was used to generate receptor-based pharmacophore model in Discovery Studio (DS). In parallel, pharmacophore models were also generated using ligand-based approach (HypoGen module in DS). Statistically significant models were generated (r(2) = 0.85) which were found to be predictive as indicated from internal and external cross-validations. The model was used as a query tool to search Zinc and Maybridge databases to identify lead compounds and predict their activity in silico. Database searching retrieved many potential lead compounds having better estimated IC50 values than the training set compounds. These compounds were then evaluated for their drug-likeliness and pharmacokinetic properties using DS. Few selected compounds were then docked into the crystal structure of enoyl-ACP reductase using Dock 6.5. Most compounds were found to have high score values, which was found to be consistent with the results from pharmacophore mapping. Additionally, molecular docking provided useful insights into the nature of binding of the identified hit molecules. In summary, we show a useful strategy employing ligand- and structure-based approaches (pharmacophore modeling coupled with molecular docking) to identify new enoyl- ACP reductase inhibitors for antimycobacterial chemotherapy.

Quantum mechanical scoring: structural and energetic insights into cyclin-dependent kinase 2 inhibition by pyrazolo[1,5-a]pyrimidines.

A quantum mechanics (QM)-based scoring function has been applied to complexes of cyclin-dependent kinase 2 (CDK2) and thirty-one pyrazolo[1,5-a]pyrimidine-based inhibitors and their bioisosteres. A hybrid three-layer QM/MM setup (DFT-D/PM6-D3H4X/AMBER in generalized Born solvent) was used here for the first time as an extension of our previous full QM and SQM/MM (SQM means semiempirical QM) approaches. Two approaches to obtain the structures of the CDK2/inhibitor complexes were examined: i) building the modifications from one X-ray structure available coupled with a conformational search and ii) docking the compounds into CDK2. The QM-based scoring entailed a QM/SQM/MM optimization followed by calculations of the binding scores which were subsequently correlated with the experimental binding free energies. The correlation for the building protocol was good (r(2) = 0.64, predictive index = 0.81), whereas the docking approach failed. A decomposition of the interaction energies to ligand fragments enabled us to rationalize the differences in the binding affinities. In conclusion, we have developed and refined a QM-based scoring protocol and successfully applied it to reproduce the binding affinities in congeneric series of CDK2 inhibitors and to rationalize their potency. We thus propose that such a tool can be used in computer-aided rational drug design.

Microwave-assisted synthesis, molecular docking and antitubercular activity of 1,2,3,4-tetrahydropyrimidine-5-carbonitrile derivatives.

Based on bioisosteric similarities with isoniazid, a series of 1,2,3,4-tetrahydropyrimidine-5-carbonitrile derivatives has been designed. The target compounds have been synthesized by multicomponent reaction which involves one-pot organic reactions using ethylcyanoacetate, urea/thiourea and arylaldehydes in presence of ethanolic K(2)CO(3). Two methodologies, conventional and microwave-assisted, have been adopted for the synthesis. The later strategy gave high yields in less than 10 min as compared to long hours using the former approach. Molecular docking of the target compounds into the enzyme Mycobacterium tuberculosis enoyl reductase (InhA) revealed important structural information on the plausible binding interactions. Major binding interactions were found to be of dispersion type (residues Tyr158, Ile215, Met103 and Met199) and a hydrogen bond with Tyr158. Binding poses of the all the compounds were energetically favorable and showed good interactions with the active site residues. Few selected compounds were also evaluated for antitubercular activity in vitro against drug-sensitive M. tuberculosis H37Rv strain and clinically isolated S, H, R and E resistant M. tuberculosis by luciferase reporter phage (LRP) assay method. Some compounds displayed promising antimycobacterial activity comparable or less than the standard drugs isoniazid and rifampicin.

Discovery of novel acyl coenzyme a: cholesterol acyltransferase inhibitors: pharmacophore-based virtual screening, synthesis and pharmacology.

The present study describes ligand-based pharmacophore modeling of a series of structurally diverse acyl coenzyme A cholesterol acyltransferase inhibitors. Quantitative pharmacophore models were generated using HypoGen module of Discovery Studio 2.1, whereby the best pharmacophore model possessing two hydrophobic, one ring aromatic, and one hydrogen bond acceptor feature for inhibition of acyl coenzyme A cholesterol acyltransferase showed a very good correlation coefficient (r = 0.942) along with satisfactory cost analysis. Hypo1 was also validated by test set and cross-validation methods. Developed models were found to be predictive as indicated by low error values for test set molecules. Virtual screening against Maybridge database using Hypo1 was performed. The two most potent compounds (47 and 48; predicted IC50 = 1 nM) of the retrieved hits were synthesized and biologically evaluated. These compounds showed 86% and 88% inhibition of acyl coenzyme A cholesterol acyltransferase (at 10 µg/mL) with IC50 value of 3.6 and 2.5 nM, respectively. As evident from the close proximity of biological data to the predicted values, it can be concluded that the generated model (Hypo1) is a reliable and useful tool for lead optimization of novel acyl coenzyme A cholesterol acyltransferase inhibitors.

Synthesis and antihyperlipidemic activity of some novel 4-(substitutedamino)-5-substituted-3-mercapto- (4H)-1,2,4-triazoles.

Hyperlipidemia is considered one of the key factors for cardiovascular diseases. Based on earlier work on a series of 5-alkyl-4-aryl-3-mercapto-(4H)-1,2,4-triazoles, for further lead modification, a series of 4-(substituted)amino-5-substituted-3-mercapto-(4H)-1,2,4-triazoles was designed. Target compounds were synthesized by the well known Hoggarth synthesis of substituted 1,2,4-triazoles. Synthesized compounds were screened for lipid lowering activity using the "Poloxamer 407 induced hyperlipidemia in rats" model at a dose of 100 mg/kg p.o. Compounds were found to alter serum lipid levels significantly. Most of the compounds significantly reduced serum cholesterol and triglyceride levels. Some of the compounds were found to reduce triglycerides and elevate high density lipoprotein (HDL) levels more than the standard drug atorvastatin (CAS 134523-03-8). Compounds with chloro substitution on aryl rings were found more active in reducing serum lipid levels than other substitutions.

Design, synthesis and histamine H1-receptor antagonistic activity of some novel 4-amino-2-(substituted)-5-(substituted) aryl-6-[(substituted aryl) amino] pyrimidines.

A series of 4-amino-2-(substituted)-5-(substituted)aryl-6-[(substituted)aryl)-amino]pyrimidines was designed based on the triangular pharmacophoric requirements for histamine H1-receptor antagonists. The designed molecules were synthesized by condensation of arylacetonitriles with respective arylisothiocyanates to form corresponding acrylonitriles followed by cyclocondensation with carboxamidines to afford substituted pyrimidines. All compounds were screened for their histamine H1-receptor antagonistic activity using the model "Inhibition of the isotonic contraction induced by histamine on isolated guinea pig ileum". Target compounds were also evaluated for their sedative potential as well as their anticholinergic activities as these two are known to be the common adverse effects of histamine H1-receptor antagonists. Compounds 2h, 2i, 2j and 2k exhibited potent histamine H1-receptor antagonistic activity, which was found to be comparable with the standard drug, cetirizine (CAS 83881-51-0) and more potent than the conventional drug mepyramine (CAS 91-84-9). Some of the compounds have displayed very low sedative potential compared to diphenhydramine (CAS 58-73-1), but was found higher than cetirizine. None of them showed anticholinergic activity indicating potentialities of this series to be developed as second-generation histamine H1-receptor antagonists.

QSAR Study on a Series of Protein Tyrosine Phosphatase 1B Inhibitors.

As a therapeutic target, protein tyrosine phosphatase 1B (PTP1B) has received considerable attention for the treatment of diabetes mellitus. A QSAR study using substituted monocyclic and polycyclic thiophene derivatives, recently reported as potent PTP1B inhibitors, was carried out. More than 60 physicochemical descriptors were calculated which underwent rational selection before their use in derivation of QSAR models. Statistically significant equations were generated using multiple linear regression analysis. External validation of the derived models with test set compounds proved good predictability of the models. Interpretation of the results revealed lipophilicity as a key regulatory feature which affects PTP1B inhibition along with several electronic and steric parameters. The study provides an important platform upon which novel rationally designed molecules can be synthesized with cautious optimism.

HDL elevation and lipid lowering therapy: current scenario and future perspectives.

High density lipoprotein (HDL) has proven its role in reverse cholesterol transport and cellular cholesterol efflux thus acting as a protective factor against atherogenic cardiovascular diseases. The article focuses primarily on structure and function of genes influencing HDL metabolism. Various novel targets involve liver X receptor, retinoid X receptor, peroxisome proliferators activated receptor agonists and apoA-I mimetics. New molecules targeting these nuclear receptors are described. Phospholipid transfer protein and scavenger receptor B1 are also attractive targets in HDL metabolism. ATP-Binding Cassette transporter A1 and several lipases also play a crucial role in HDL metabolism and are very useful target for atherogenic dyslipidemia. Cholesteryl ester transfer protein inhibitors have shown great promise as possible drug candidates of future. Notably, JTT-705 (Japan Tobacco, Roche) is of great interest in spite of withdrawal of torcetrapib. Considering modest effect of currently available therapeutic options on HDL, these novel HDL elevating targets are doubtlessly the target for future atherosclerotic intervention.

Novel targets for the treatment of atherosclerosis.

Atherosclerosis remains the leading cause of death in developed countries and thus demands the development of safe therapeutic treatments. Novel risk factors, in addition to the traditional targets, are being assessed. The significance of inflammation in atherosclerotic plaque development has become indisputable. A large number of published studies support the fact that investigations of the inflammatory aspects of atherosclerosis will be the target for future development. The C-reactive protein in particular has drawn specific attention due to its role as an inflammatory marker of atherosclerosis. Novel targets for atherosclerotic intervention include inhibitors of cholesterol synthesis and absorption such as acyl-coenzyme A:cholesterol acyltransferase, acyl-coenzyme A:diacylglycerol acyltransferase and cholesteryl ester transfer protein inhibitors, potential novel antioxidants other than anti-inflammatory peroxisome proliferator activated receptor agonists, and apolipoprotein A-I mimetic peptides.

Synthesis of new chemical entities from paracetamol and NSAIDs with improved pharmacodynamic profile.

It was envisaged to combine high antipyretic activity of paracetamol into commonly used NSAIDs. To achieve this goal new chemical entities were synthesized by chemically combining paracetamol and NSAIDs, and biologically evaluated for their antipyretic, analgesic, anti-inflammatory and ulcerogenic potential. The acid chloride of parent NSAIDs was reacted with excess of p-aminophenol to yield the desired p-amidophenol derivatives (1B-7B). Acetate derivatives (1C-7C) of these phenols (1B-7B) were also prepared by their treatment with acetic anhydride, in order to see the impact of blocking the free phenolic group on the biological activity of the derivatives. All the synthesized p-amidophenol derivatives showed improved antipyretic activity than paracetamol with retention of anti-inflammatory activity of their parent NSAIDs. These compounds elicited no ulcerogenicity unlike their parent drugs.

Recent developments in the treatment of atherosclerosis.

Atherosclerosis is one of the most frequent causes of cardiac arrest. The major cause of this disease is high concentrations of lipid in the blood. Medicinal agents so far have been quite successful in the management of hyperlipidemia. Among the several widely used drugs, (fibrates, statins and niacin) statins are the most frequently prescribed in many forms of hyperlipidemia. Recently, statins have been found to produce serious toxicities, which are rare but can be potentially harmful and are noise concern for the immediate need to develop some new chemical entities in this category. This review is primarily concerned with recent developments in atherosclerotic drug discovery including novel inhibitors of cholesterol biosynthesis, cholesterol absorption inhibitors and antioxidants. The review also focuses on possible future targets including gene therapy.