Modulating Antimicrobial Efficacy Through Hybrid Compounds: Novel Linkers and Scaffold Switching from Isoniazid to 3,5-Dinitrobenzohydrazide

Abstract

Tuberculosis and non-tuberculous mycobacterial infections present significant treatment challenges due to rising drug resistance. Building on our previous success with (E)-2-(2-isonicotinoylhydrazineylidene)-N-phenylpropanamides,1 we expanded this chemical space by linking bioactive hydrazide pharmacophores via oxocarboxylic acid-based linkers (pyruvic, glyoxylic, and 4-formylbenzoic acid; Fig. 1) while incorporating various antimicrobial scaffolds2 and additional amine derivatives. A strategic shift from the traditional isoniazid (INH) core to 3,5-dinitrobenzohydrazide, a proven building block for antimycobacterial agents, was also explored (Fig. 1) to enhance activity and circumvent common INH resistance mechanisms. The novel hydrazide-hydrazone derivatives were evaluated against a panel of mycobacteria, including drug-resistant strains, as well as against bacteria, human pathogenic fungi, for toxicity and mechanism of action. The most potent compounds exhibited MIC values as low as <=0.25 µM against Mycobacterium tuberculosis and showed significant activity against M. kansasii. Structural modifications had a pronounced impact on antimycobacterial potency, and key structure-activity relationships (SARs) were identified, providing insights for future optimization.