Synthesis, evaluation and in silico molecular modeling of pyrroyl-1,3,4-thiadiazole inhibitors of InhA

Surflex docking and CoMFA studies carried out for newly synthesized pyrrolyl aryloxy 1,3,4-thiadiazoles. Enoyl ACP reductase from Mycobacterium tuberculosis used for Surflex-Dock study. [Display omitted] •Design and synthesis of some pyrrolyl aryloxy 1,3,4-thiadiazoles.•Synthesized compounds screened for antitubercular activity using MABA method against Mycobacterium tuberculosis H37Rv.•Key interactions observed by Surflex docking and CoMFA analysis carried out to understand the SAR.•A bulky groups and H-bond acceptors are important for antitubercular activity.•Inhibitors were active against Mycobacterium tuberculosis and non toxic. Enoyl acyl carrier protein reductase (ENR)is an essential type II fatty acid synthase (FAS-II) pathway enzyme that is an attractive target for designing novel antitubercular agents.Herein, we report sixty-eight novel pyrrolyl substituted aryloxy-1,3,4-thiadiazoles synthesized by three-step optimization processes. Three-dimensional quantitative structure–activity relationships (3D-QSAR) were established for pyrrolyl substituted aryloxy-1,3,4-thiadiazole series of InhA inhibitors using the comparative molecular field analysis (CoMFA).Docking analysis of the crystal structure of ENR performed by using Surflex-Dock in Sybyl-X 2.0 software indicates the occupation of pyrrolyl substituted aryloxy 1,3,4-thiadiazole into hydrophobic pocket of InhA enzyme. Based on docking and database alignment rules, two computational models were established to compare their statistical results. The analysis of 3D contour plots allowed us to investigate the effect of different substituent groups at different positions of the common scaffold. In vitro testing of ligands using biological assays substantiated the efficacy of ligands that were screened through in silico methods.