Shailesh V. Jain

Recent advances and therapeutic journey of coumarins: current status and perspectives

Coumarins are oxygen-containing molecules with specific benzopyrone nucleus. Different coumarins are identified as antineurodegeneratives, anticoagulants, antioxidants, antimicrobials, anticancers, antivirals, antidiabetics, antidepressants, supramoleculars, antiparasitics, anti-inflammatory, analgesics, biological stains, pathological probes and diagnostics. Coumarins have received more attention as compared to 1-azacoumarins. Many attempts have been made for the comparison of both the systems at different stages to discover novel synthetic methodologies, reactivity strategies and biological activities. Translation of current knowledge into novel potent lead compounds and repositioning of well-known compounds for the treatment of different acute and chronic diseases are the current challenges of coumarins. This review article focusses on the occurence, synthesis and specific biological activities of various coumarin derivatives. Some novel research approaches are also described for the discovery and development of new synthetic strategies that could help in structure–activity relationship (SAR) studies. Cellular and molecular mechanisms of coumarins involved in SAR studies are also described.

2D, 3D-QSAR and docking studies of 1,2,3-thiadiazole thioacetanilides analogues as potent HIV-1 non-nucleoside reverse transcriptase inhibitors

Background The discovery of clinically relevant inhibitors of HIV-RT for antiviral therapy has proven to be a challenging task. To identify novel and potent HIV-RT inhibitors, the quantitative structure–activity relationship (QSAR) approach became very useful and largely widespread technique forligand-based drug design. Methods We perform the two- and three-dimensional (2D and 3D) QSAR studies of a series of 1,2,3-thiadiazole thioacetanilides analogues to elucidate the structural properties required for HIV-RT inhibitory activity. Results The 2D-QSAR studies were performed using multiple linear regression method, giving r2 = 0.97 and q2 = 0.94. The 3D-QSAR studies were performed using the stepwise variable selection k-nearest neighbor molecular field analysis approach; a leave-one-out cross-validated correlation coefficient q2 = 0.89 and a non-cross-validated correlation coefficient r2 = 0.97 were obtained. Docking analysis suggests that the new series have comparable binding affinity with the standard compounds. Conclusions This approach showed that hydrophobic and electrostatic effects dominantly determine binding affinities which will further useful for development of new NNRTIs.

3D-QSAR Study of Indol-2-yl Ethanones Derivatives as Novel Indoleamine 2,3-Dioxygenase (IDO) Inhibitors

3D-QSAR approach using kNN-MFA was applied to a series of Indol-2-yl ethanones derivatives as novel IDO inhibitors. For the purpose, 22 compounds were used to develop models. To elucidate the structural properties required for IDO inhibitory activity, we report here k-nearest neighbor molecular field analysis (kNN-MFA)-based 3D-QSAR model for Indol-2-yl ethanones derivatives as novel IDO inhibitors. Overall model classification accuracy was 76.27% (q2 = 0.7627, representing internal validation) in training set and 79.35% (pred_r2 = 0.7935, representing external validation) in test set using sphere exclusion and forward as a method of data selection and variable selection, respectively. Contour maps using this approach showed that hydrophobic and steric effects dominantly determine binding affinities. The information rendered by 3D-QSAR model may lead to a better understanding of structural requirements of IDO inhibitors and can help in the design of novel potent molecules.

2,4-Dihydropyrano[2,3-c]pyrazole: Discovery of new lead as through pharmacophore modelling, atom-based 3D-QSAR, virtual screening and docking strategies for improved anti-HIV-1 chemotherapy

Abstract Due to the AIDS crisis, development of new, selective and safe non-nucleoside reverse transcriptase inhibitors (NNRTIs) remains a high priority for medical research. The discovery of potential lead compounds by analogue based design studies was accomplished using 3D-QSAR and pharmacophore modelling of non-nucleoside reverse transcriptase inhibitors. A series of 24 diarylaniline analogues as NNRTIs were used to develop an atom based pharmacophore model. A five-point pharmacophore with two hydrogen bond acceptors (A), one donor (D) and two aromatic rings (R) as pharmacophore features was selected and exhibited a statistically significant correlation coefficient of R2 = 0.90 for the training set compounds and Q2 = 0.81 for a randomly chosen test set of compounds. The derived pharmacophore was used as a template to screen a specs database. The retrieved hits were progressively passed through filters, such as the predicted activity, fitness score, Lipinski screen and docking scores. The surviving 12 hits exhibited new scaffold (i.e., 2,4-dihydropyrano[2,3-c]pyrazole) for anti-HIV-1 chemotherapy as non-nucleoside reverse transcriptase inhibitors.

Structure based lead optimization approach in discovery of selective DPP4 inhibitors.

Diabetes mellitus is a chronic progressive metabolic disorder that has profound consequences for individuals, families, and society. To date, main available oral antidiabetic medications target either insulin resistance (metformin, glitazones), or insulin deficiency (sulfonylureas, glinides), but leading to shortfalls in medication. Advancement in modern oral hypoglycemic agents may be encouraged with or in place of traditional therapies. The lower risk for hypoglycemic events as compared with other insulinotropic or insulin-sensitizing agents make DPP-4 inhibitors very promising candidates for a more physiological treatment of type-2 diabetes. Only some DPP-4 inhibitors are currently used for the treatment of type 2 diabetes (T2DM) and various inhibitors currently undergoing animal and human testing. A number of catalytically active DPPs distinct from DPP-4 (DPP II, FAP, DPP-8, and DPP-9) have been described that is associated with side-effect and toxicity. To discover potent and selective and safer drugs in a shorter time frame and with reduced cost it requires using an innovative approach for designing novel inhibitors. This review article focuses on the status of advanced lead candidates of DPP group and their binding affinity with the active site residue of target structure which help in discovery of potent and selective DPP-4 inhibitors by lead optimization approach.

Atom-based pharmacophore modeling, CoMFA/CoMSIA-based 3D-QSAR studies and lead optimization of DPP-4 inhibitors for the treatment of type 2 diabetes

A dipeptidyl peptidase-4 (DPP-4) enzyme is responsible for degradation of GLP-1 incretin hormone and in cooperates in glucose metabolism. Inhibition of DPP-4 is a promising new approach for the treatment of type-2 diabetes with low risk of hypoglycemia. An analog-based design study was performed using pharmacophore modeling and 3D-QSAR to design potential lead compounds. A five-point pharmacophore model with two hydrogen bond acceptors (A), one hydrophobic (H), one positive (P), and one aromatic rings (R) as pharmacophore features was generated using 38 azabicyclo-derived dipeptidyl peptidase-IV inhibitors. The validated pharmacophore alignment was used for CoMFA and CoMSIA 3D-QSAR model development. The models generated from SYBYL shown a high cross-validated r2 value of 0.63 and 0.61 for CoMFA and CoMSIA models. Systematic pharmacophore-based screening protocol was used to screen commercial databases. Hits retrieved were progressively passed through filters like predicted activity, fitness score, Lipinski screen, and docking scores. The survived seven hits were further visually analyzed which shows that all hits contain the same scaffold of piperazinum ring which can be replaced by the azabicyclo ring in the existing lead which may increase the potency of DPP-4 inhibitors.Graphical Abstract

3D-QSAR pharmacophore modeling and in silico screening of phospholipase A2α inhibitors

Cytosolic phospholipase A2α have emerged as an attractive target for the development of analgesic and anti-inflammatory drugs. 3D-QSAR pharmacophore model was developed, based on previously reported 28 indole-5-carboxylic acids, and used to understand the structural factors affecting the inhibitory potency of these derivatives. Hydrogen bond acceptor, negative charge, and aromatic effects contribute to the inhibitory activity. The model was employed as a 3D search query to screen SPECS database to select new scaffolds. Finally, docking studies lead to the identification of fourteen potential phospholipase A2α inhibitors. Subsequent ADME studies revealed the pharmacokinetic efficiency of these compounds.

Synthesis, Characterization, and Antihypertensive Evaluation of Some Novel 2,2,8,8-Tetramethyl-2,3,7,8-tetrahydro-4,6-diamino-3,7-dihydroxy-6,7-epoxy-benzo-[1,2-b:5,4-b′]dipyran Derivatives

A series of 2,2,8,8-tetramethyl-2,3,7,8-tetrahydro-4,6-diamino-3,7-dihydroxy-6,7-epoxy-benzo-[1,2-b:5,4-b′]dipyran derivatives 7a–e and 8a–e were synthesized from resorcinol. All the synthesized compounds were characterized by FTIR, mass spectra, and 1H NMR. These compounds were evaluated for antihypertensive activity using Wister Albino Rat model. Direct antihypertensive activity was performed using the instrument BIOPAC System MP-36 Santa Barbara, California, for recording blood pressure response. Among the title compounds, compounds 7b, 7c, and 7d showed potent antihypertensive activity and other compounds were also found to exert low and moderate antihypertensive activity. The relaxant potency in rat aorta and trachea was used for biological characterization of the benzopyrans. Structure-activity relationships study was investigated around position-4 of the benzopyran nucleus.