Discovery of newer pyrazole derivatives with potential anti-tubercular activity via 3D-QSAR based pharmacophore modelling, virtual screening, molecular docking and molecular dynamics simulation studies

Tuberculosis is one of the leading causes of death of at least one million people annually. The deadliest infectious disease has caused more than 120 million deaths in humans since 1882. The cell wall structure of Mycobacterium tuberculosis is important for survival in the host environment. InhA is the foremost target for the development of novel anti-tubercular agents. Therefore, we report pharmacophore-based virtual screening (ZINC and ASINEX databases) and molecular docking study (PDB Code: 4TZK) to identify and design potent inhibitors targeting to InhA. A five-point pharmacophore model AADHR_1 (with R 2 = 0.97 and Q 2 = 0.77) was developed by using 47 compounds with its reported MIC values. Further, to identify and design potent hit molecules based on lead identification and modification, generated hypothesis employed for virtual screening using ZINC and ASINEX databases. Predicted pyrazole derivatives further gauged for drug likeliness and docked against enoyl acyl carrier protein reductase to categorize the essential amino acid interactions to the active site of the enzyme. Structure elucidation of these synthesized compounds was carried out using IR, MS, 1H-NMR and 13C-NMR spectroscopy. Amongst all the synthesized compounds, some of the compounds 5a, 5c, 5d and 5e were found to be potent with their MIC ranging from 2.23 to 4.61 µM. Based on preliminary anti-tubercular activity synthesized potent molecules were further assessed for MDR-TB, XDR-TB and cytotoxic study. Graphical abstract