Structure-based design, synthesis, and biological evaluation of hydrazide-linked benzyl ether analogues as inhibitors of Mycobacterium tuberculosis

Aims To design, synthesize, and assess novel hydrazide-linked benzyl ether analogues as potential inhibitors of Mycobacterium tuberculosis.Materials and methods A series of hydrazide-linked benzyl ether analogues (8a–p) were synthesized, and their antimycobacterial activity was determined by minimum inhibitory concentrations (MICs) against M. tuberculosis. Molecular docking and molecular dynamics simulations were performed to investigate their predicted binding interactions and stability within the InhA active site. Time-kill kinetics and cytotoxicity assays evaluated the bactericidal potential and selectivity of the most active compound toward mammalian cells.Results The compounds exhibited MIC values ranging from 1 to >64 µg/mL against M. tuberculosis, with several derivatives showing no detectable activity at the highest tested concentration of 64 µg/mL. Time-kill and cytotoxicity studies provided evidence of bactericidal activity and a favorable preliminary selectivity profile for the evaluated compound.Conclusion The synthesized hydrazide-linked benzyl ether derivatives exhibited promising antimycobacterial activity, identifying this scaffold as a potential starting point for the development of novel antitubercular agents. The molecular docking findings provided a plausible structural basis for their potential interaction with InhA; however, experimental biochemical studies are required to confirm direct InhA inhibition.