Structure-activity relationship-driven lead optimization of pyrazole hydrazide-hydrazone analogues as potent antimycobacterial agents: in vitro and in silico studies.

A distinct series of novel pyrazole hydrazide-hydrazone analogues, developed through a structure-activity relationship-driven lead optimization approach, and evaluated for their antitubercular activity. Among the evaluated compounds, within the series, compounds 5l and 5m demonstrated notable potency, with MIC values of 0.5 and 1 μg/mL, respectively, along with efficacy against drug-resistant Mycobacterium tuberculosis strains and favorable SI values 23-24. To elucidate the possible mechanism of action, the lead compounds were subjected to molecular docking and 100 ns molecular dynamics simulations, which strongly implicated enoyl-ACP reductase (InhA) as the most probable biological target. Furthermore, in silico ADME analysis revealed favorable pharmacokinetic properties and drug-likeness profiles for the most active derivatives. Collectively, these results highlight the potential of these novel pyrazole hydrazide-hydrazone scaffolds as promising lead candidates for the development of next-generation antitubercular agents, particularly against drug-resistant strains.