Synthesis and evaluation of novel 3,5-dinitrobenzoyl substituted amino acid hydrazides against Mycobacterium...

Multidrug-resistant tuberculosis (MDR-TB) represents an urgent unmet clinical need, with current regimens limited by prolonged duration, toxicity, and escalating resistance. We report the design, synthesis, and biological evaluation of 43 novel 3,5-dinitrobenzoyl amino acid hydrazide analogues against wild-type and multidrug-resistant strains of Mycobacterium tuberculosis. Systematic variation of both the amino acid side chain and the aryl hydrazide substituent revealed that hydrophobic, extended side chains confer superior antimycobacterial potency, whilst the influence of the hydrazide substituent appears context-dependent, modulated by the steric demands of the amino acid side chain. Cytotoxicity against mammalian cells was observed for several potent analogues, representing an early-stage optimisation challenge with clearly identified structure-dependent separability. Molecular docking against decaprenylphosphoryl-β-d-ribose 2'-epimerase (DprE1) is presented as a hypothesis-generating framework to rationalise key SAR trends. These findings establish a refined SAR landscape that will guide future structural optimisation of this promising antitubercular scaffold.