Exploration of pyrazole-based pyridine-4-carbohydrazide derivatives as drug-resistant Mtb agents: design, synthesis, biological evaluation, and in-silico studies

Development of new effective drugs against multidrug resistant Mycobacterium tuberculosis is the need of the hour to combat tuberculosis (TB) disease. Pyridine-4-carbohydrazide and substituted pyrazole aldehydes were used to synthesize target molecules (6a-r) which were evaluated against H37Rv and drug-resistant TB strains. Time kill kinetics assay was performed to check bactericidal/bacteriostatic effect, molecular docking, dynamics simulation over 100 ns was performed against enoyl acyl carrier protein reductase (InhA) along with QSAR, ADMET profile prediction. All compounds displayed excellent MICs in the range of 0.125-16 µg/mL. The most potent compound, 6q, with an MIC of 0.125 µg/mL showed bactericidal effect and was effective on ethambutol and streptomycin resistant Mtb strains with an MIC of 0.03 µg/mL and rifampicin resistant Mtb strain with an MIC of 0.25 µg/mL. The pyrazole clubbed with pyridine-4-carbohydrazide is a potential scaffold for further exploration as anti-TB agent.