Design, Synthesis and Building a QSAR model for the inhibition of Mycobacterium tuberculosis by Pyrazoline derivatives

Abstract

A series of chalcone annulated pyrazoline conjugates have recently been synthesized from our laboratory and identified as possible “LEAD”s against Mycobacterium tuberculosis (MTB) through an in-silico study. The MTB enoyl acyl carrier protein reductase (InhA) plays a vital role in the MTB fatty acid synthesis pathway as essential in the mycolic acid biosynthesis. Therefore, inhibition of InhA could block the biosynthesis of mycolic acids, resulting in mycobacteria death. To further explore the potency of the compounds, a quantitative structure-activity relationship (QSAR) study is carried out. To develop a new pharmacophoric model for this inhibition, a QSAR approach of reported pyrazoline derivatives against tuberculosis has been studied. Multiple linear regression analysis was performed to derive the QSAR models, which were further evaluated internally as well as externally for the prediction of activity. The accurate MIC values (µg/ml) were collected for 23 pyrazoline analogs, and other descriptor parameters, such as log p (o/w), MR, DM, EELE, LUMO, HOMO, and TPSA were compared with these analogs. A training set of 23 analogs, all having a common pyrazoline moiety, provided a cross-validated correlation coefficient (r2) value of 0. 45112 and root mean square error (RMSE) value of 0. 0.27760. Moreover, based on this QSAR study, we have hypothetically estimated the predicted pMIC50 by using trainpred.fit file from Molecular Operating Environment 2009.10 software for the newly synthesized test set i.e., six chalcone based pyrazoline compounds. The resulting QSAR model generated from the present study may be useful in the design of a similar group of pyrazoline analogs as anti-tubercular agents.