@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 {46358, title = {Recursive partitioning analysis and anti-tubercular screening of 3-aminopyrazine-2-carbohydrazide derivatives}, journal = {Letters in Drug Design \& Discovery}, volume = {16}, year = {2019}, month = {APR}, pages = {1264-1275}, type = {Article}, abstract = {

Background: Treating tuberculosis is a challenge due to the development of drug resistance. Hence, it is imperative to develop novel leads having high potency and efficacy to curb drug resistance. Methods: The present research work is focused on microwave-assisted synthesis of novel twenty-six 3-amino-N{\textquoteright}-benzylidenepyrazine-2-carbohydrazide derivatives (3a-z), where, lyophilization technique was used for isolation of the major intermediate, 3-aminopyrazin-2-carbohydrazide. All synthesized compounds were subjected for anti-tubercular screening against Mycobacterium tuberculosis H37Ra by using XTT Reduction Menadione Assay (XRMA) protocol. Results: Out of 26 synthesized compounds, four N{\textquoteright}-substitutedbenzaldehyde-3-amino-pyrazine-2-carbohydrazide derivatives viz. 3i, 3j 3v and 3z showed significant activity against M. tuberculosis H37Ra. The compounds 3i, 3j, 3v and 3z showed 99, 98, 92 and 87 \% inhibition respectively as compared to 94\% inhibition shown by the standard drug rifampicin. The MIC and IC50 values were in the range of 24.3-110 and 5.9-20.8 mu g/ml respectively. Conclusion: A classification model called Recursive Partitioning (RP) based on binary Quantitative Structure-Activity Relationship (QSAR) was derived for the establishment of structure-activity relationship (SAR). The predictions derived on the basis of RP model were found to be in agreement with anti-tubercular screening data.

}, keywords = {3-aminopyrazine, anti-tubercular activity, Carbohydrazide, lyophilization, QSAR, recursive partitioning}, issn = {1570-1808}, doi = {10.2174/1570180816666190329222636}, author = {Miniyar, Pankaj and Mahajan, Anand and Anuse, Dattatray and Kumar, Ashish and Barmade, Mahesh and Sarkar, Dhiman and Arkile, Manisha and Khedkar, Vijay} } @article {47579, title = {2D-QSAR modeling and two-fold classification of 1,2,4-triazole derivatives for antitubercular potency against the dormant stage of Mycobacterium tuberculosis}, journal = {Molecular Diversity}, volume = {26}, year = {2021}, month = {APR}, pages = {1227-1242}, type = {Article}, abstract = {

The dormant or latent form of Mycobacterium tuberculosis (MTB) is not killed by the conventional antitubercular drugs. The treatment of latent TB is essential to reduce the period of treatment as well as incidences of drug resistance. In this background, we have made an attempt to develop the quantitative structure-activity relationship models (QSAR: regression and classification based) against the dormant form of MTB and later used the developed classifier models (linear discriminant analysis (LDA) and random forest (RF)) for the two-fold classifications. The logic of applying this concept of two-fold classification for the MTB modeling is to increase the confidence of correct classification. The 2D-QSAR modeling suggested the contribution of burden eigen, edge adjacency, van der Waals (vdW) surface area, topological charge, and pharmacophoric indices in predicting the antitubercular activity against the dormant MTB. The prediction qualities of the training and test sets were found to be moderate and good, according to the mean absolute error (MAE)-based criteria{\textquoteright}s. The LDA and RF models unveiled the importance of burden eigen, edge adjacency, Geary autocorrelation, and drug-like indices as discriminating features to differentiate the antitubercular compounds into higher and lower active groups. The LDA model showed the classification accuracies of 85.14\% and 87.10\% for the training and test sets, while the RF model exhibited the accuracies of 100.00\% and 80.65\% for both the sets. The descriptors selected in the final models are only two-dimensional (2D), which are easy to compute and does not require computationally expensive steps of structure conversion, optimization, and energy minimization mandatorily needed before the computation of 3D descriptors. These models could be used for identifying and selection of higher active compounds against the dormant form of the MTB.

}, keywords = {Classification models, Dormant TB, Linear discriminant analysis (LDA), Mycobacterium tuberculosis (MTB), Nonlinear modeling, QSAR, Random forest (RF)}, issn = {1381-1991}, doi = {10.1007/s11030-021-10254-y}, author = {Aher, Rahul Balasaheb and Sarkar, Dhiman} } @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} } @article {47713, title = {On the use of electronegativity and electron affinity based pseudo-molecular field descriptors in developing correlations for quantitative structure-activity relationship modeling of drug activities}, journal = {Chemical Biology \& Drug Design}, volume = {98}, year = {2021}, month = {AUG}, pages = {258-269}, type = {Article}, abstract = {For quantitative structure-activity relationship (QSAR) modeling in ligand-based drug discovery programs, pseudo-molecular field (PMF) descriptors using intrinsic atomic properties, namely, electronegativity and electron affinity are studied. In combination with partial least squares analysis and Procrustes transformation, these PMF descriptors were employed successfully to develop correlations that predict the activities of target protein inhibitors involved in various diseases (cancer, neurodegenerative disorders, HIV, and malaria). The results show that the present QSAR approach is competitive to existing QSAR models. In order to demonstrate the use of this algorithm, we present results of screening naturally occurring molecules with unknown bioactivities. The pIC(50) predictions can screen molecules that have desirable activity before assessment by docking studies.}, keywords = {drug discovery, electron affinity, Electronegativity, molecular field descriptors, partial least squares, QSAR}, issn = {1747-0277}, doi = {10.1111/cbdd.13895}, author = {Kunde, Pushkar D. and Ramkumar, Sudha and Kamble, Sanjay P. and RaviKumar, Ameeta and Kulkarni, Bhaskar D. and Kumar, V. Ravi} }