@article { ISI:000319417100005, title = {Design, synthesis, structural characterization by IR, 1H, 13C, 15N, 2D-NMR, X-ray diffraction and evaluation of a new class of phenylaminoacetic acid benzylidene hydrazines as pfENR inhibitors}, journal = {Chemical Biology \& Drug Design}, volume = {81}, number = {6}, year = {2013}, month = {JUN}, pages = {715-729}, publisher = {WILEY-BLACKWELL}, address = {111 RIVER ST, HOBOKEN 07030-5774, NJ USA}, abstract = {

Recent studies have revealed that plasmodial enoyl-ACP reductase (pfENR, FabI), one of the crucial enzymes in the plasmodial type II fatty acid synthesis II (FAS II) pathway, is a promising target for liver stage malaria infections. Hence, pfENR inhibitors have the potential to be used as causal malarial prophylactic agents. In this study, we report the design, synthesis, structural characterization and evaluation of a new class of pfENR inhibitors. The search for inhibitors began with a virtual screen of the iResearch database by molecular docking. Hits obtained from the virtual screen were ranked according to their Glide score. One hit was selected as a lead and modified to improve its binding to pfENR; from this, a series of phenylamino acetic acid benzylidene hydrazides were designed and synthesized. These molecules were thoroughly characterized by IR, 1H, 13C, 15N, 2D-NMR (COSY, NOESY, 1H-13C, 1H-15N HSQC and HMBC), and X-ray diffraction. NMR studies revealed the existence of conformational/configurational isomers around the amide and imine functionalities. The major species in DMSO solution is the E, E form, which is in dynamic equilibrium with the Z, E isomer. In the solid state, the molecule has a completely extended conformation and forms helical structures that are stabilized by strong hydrogen bond interactions, forming a helical structure stabilized by N-H...O interactions, a feature unique to this class of compounds. Furthermore, detailed investigation of the NMR spectra indicated the presence of a minor impurity in most compounds. The structure of this impurity was deduced as an imidazoline-4-one derivative based on 1H-13C and 1H-15H HMBC spectra and was confirmed from the NOESY spectra. The molecules were screened for in vitro activity against recombinant pfENR enzyme by a spectrophotometric assay. Four molecules, viz. 17, 7, 10, and 12 were found to be active at 7, 8, 10, and 12m concentration, respectively, showing promising pfENR inhibitory potential. A classification model was derived based on a binary QSAR approach termed recursive partitioning (RP) to highlight structural characteristics that could be tuned to improve activity.

}, keywords = {ADMET, docking, enoyl-ACP reductase, FabI, hydrogen bonding, NMR, phenylaminoacetic acid benzylidene hydrazine, Plasmodium falciparum, Plasmodium falciparum enoyl-ACP reductase, QSAR, recursive partitioning, X-ray diffraction}, issn = {1747-0277}, doi = {10.1111/cbdd.12118}, author = {Samal, Ramanuj P. and Khedkar, Vijay M. and Pissurlenkar, Raghuvir R. S. and Bwalya, Angela Gono and Tasdemir, Deniz and Joshi, Ramesh A. and Rajamohanan, P. R. and Puranik, Vedavati G. and Coutinho, Evans C.} } @article { ISI:000371304100013, title = {Synthesis, biological valuation, and QSAR studies of novel pyrazole bearing pyridyl oxadiazole analogues as potential antimicrobial agents}, journal = {Medicinal Chemistry Research}, volume = {25}, number = {4}, year = {2016}, month = {APR}, pages = {712-727}, publisher = {SPRINGER BIRKHAUSER}, address = {233 SPRING STREET, 6TH FLOOR, NEW YORK, NY 10013 USA}, abstract = {

A new series of 1-(2-(3-(4-nitrophenyl)-1-phenyl-1H-pyrazol-4-yl)-5-(pyridin-4-yl)-1,3,4 -oxadiazol-3(2H)-yl)-3-(aryl)prop-2-en-1-ones (5a-l) were synthesized by a simple and efficient synthetic protocol. The newly synthesized compounds were characterized by IR, H-1 NMR, C-13 NMR and Mass spectroscopy. The resulting structural diversity was screened for its antimicrobial activity the following bacterial and fungal strains: two Gram-positive bacteria [Staphylococcus aureus (MTCC-96), Streptococcus pyogenes (MTCC-442)], two Gram-negative bacteria [Escherichia coli (MTCC-443), Pseudomonas aeruginosa (MTCC-1688)] and three fungal species (C. albicans, A. niger and A. clavatus). Following this, in vitro cytotoxicity activity against HeLa cell lines was measured by MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide] assay. The observations derived from the diverse assays were utilized for building classification models based on a binary QSAR approach termed recursive partitioning (RP) analysis to probe the physic-chemical properties influencing the SAR for molecules. The decision tree derived from RP analysis could highlight structural characteristics that discriminate the actives from inactives which can serve as guide to design molecules with improved potency. In silico ADME predictions were performed to gauge their pharmacokinetic, safety and drug likeness profile.

}, keywords = {1, 3, 4-Oxadiazole, Antimicrobial activity, Cytotoxicity, Pyrazole, Pyridine, QSAR}, issn = {1054-2523}, doi = {10.1007/s00044-016-1511-4}, author = {Desai, N. C. and Kotadiya, G. M. and Trivedi, A. R. and Khedkar, Vijay M. and Jha, Prakash C.} } @article {47125, title = {In silico studies, synthesis and antitubercular activity of some novel quinoline - azitidinone derivatives}, journal = {Current Computer-Aided Drug Design}, volume = {17}, year = {2021}, month = {JAN}, pages = {134-143}, type = {Article}, abstract = {

Background: Diarylquinolines like Bedaquiline have shown promising antitubercular activity by their action of Mycobacterial ATPase. Objective: The structural features necessary for a good antitubercular activity for a series of quinoline derivatives were explored through computational chemistry tools like QSAR and combinatorial library generation. In the current study, 3-Chloro-4-(2-mercaptoquinoline-3-yl)-1-substitutedphenylazitidin-2-one derivatives have been designed and synthesized based on molecular modeling studies as anti-tubercular agents. Methods: 2D and 3D QSAR analyses were used to designed compounds having a quinoline scaffold. The synthesized compounds were evaluated against active and dormant strains of Mycobacterium tuberculosis (MTB) H37 Ra and Mycobacterium bovis BCG. The compounds were also tested for cytotoxicity against MCF-7, A549 and Panc-1 cell lines using MTT assay. The binding affinity of designed compounds was gauged by molecular docking studies. Results: Statistically significant QSAR models generated by the SA-MLR method for 2D QSAR exhibited r(2) = 0.852, q(2) = 0.811, whereas 3D QSAR with SA-kNN showed q(2) = 0.77. The synthesized compounds exhibited MIC in the range of 1.38-14.59(mu g/ml). These compounds showed some crucial interaction with MTB ATPase. Conclusion: The present study has shown some promising results which can be further explored for lead generation.

}, keywords = {combilib, Molecular docking, mycobacterial ATPase, QSAR, Quinoline}, issn = {1573-4099}, doi = {10.2174/1573409916666200129095952}, author = {Chitre, Trupti S. and Asgaonkar, Kalyani D. and Vikhe, Amrut B. and Patil, Shital M. and Garud, Dinesh R. and Khedkar, Vijay M. and Sarkar, Dhiman and Nawale, Laxman U. and Yeware, Amar} }