Design and synthesis of isoniazid-based pyrazolines as potential inhibitors of Mycobacterium tuberculosis with promising radical scavenging action: In-vitro and in-silico evaluations

In view of the devastating tuberculosis infections and emerging resistance against available drugs, novel 5-phenyl-3-(thiophen-2-yl)-4,5-dihydro-1H-pyrazol-1-yl)(pyridin-4-yl)methanones were designed and efficiently synthesized. The in-vitro biological screening of the synthesized isoniazid-based pyrazolines reveals their remarkable antimycobacterial and antioxidant ability. The pyrazoline analog 4i containing 2,4-dimethoxy phenyl substituent exhibited the highest anti-TB action against the H37Rv Mtb strain with an MIC of 6.35 μM, while the pyrazoline analog 4f with 2-nitrophenyl substituent demonstrates the highest radical quenching ability with an IC50 of 96.19 μM. Through DFT execution, the quantum-mechanical properties, reactivity indices, and molecular electrostatic potential mapping of the synthesized entities were determined, showing their optimum chemical and biological compatibility. The potent antitubercular effect of the synthesized entities was further supported by docking assessment against one of the most promising antitubercular targets, InhA (PDB Id: 2X23), displaying a significant binding range of −8.3 to −9.6 kcal/mol, and favorable binding interactions with the key residues like TYR 158, THR 196. etc. The pharmaceutical compliance of the synthesized moieties was further assessed through in-silico ADMET screening, which illustrates their excellent drug likeliness and appreciable pharmacokinetic behavior.