Design and Synthesis of Highly Active Antimycobacterial Mutual Esters of 2-(2-Isonicotinoylhydrazineylidene)propanoic Acid

• Published in: Pharmaceuticals (Basel, Switzerland) Vol. 14; no. 12; p. 1302
• Main Authors: Pflégr, Václav, Maixnerová, Jana, Stolaříková, Jiřina, Pál, Adrián, Korduláková, Jana, Trejtnar, František, Vinšová, Jarmila, Krátký, Martin
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 14.12.2021; MDPI
• Subjects: Antimicrobial agents; antimycobacterial activity; Chromatography; COVID-19; Drug resistance; enzyme inhibition; esters; InhA; isoniazid; mechanism of action; Tuberculosis; United States > US; Czech Republic; Germany; isoniazid; enzyme inhibition; esters; antimycobacterial activity; mutual prodrugs; mechanism of action; InhA
• ISSN: 1424-8247; 1424-8247
• DOI: 10.3390/ph14121302

The combination of two active scaffolds into one molecule represents a proven approach in drug design to overcome microbial drug resistance. We designed and synthesized more lipophilic esters of 2-(2-isonicotinoylhydrazineylidene)propanoic acid, obtained from antitubercular drug isoniazid, with various alcohols, phenols and thiols, including several drugs, using carbodiimide-mediated coupling. Nineteen new esters were evaluated as potential antimycobacterial agents against drug-sensitive ( .) H Rv, and . Selected derivatives were also tested for inhibition of multidrug-resistant (MDR) ., and their mechanism of action was investigated. The esters exhibited high activity against . (minimum inhibitory concentrations, MIC, from ≤0.125 μM), , as well as MDR strains (MIC from 0.25, 32 and 8 µM, respectively). The most active mutual derivatives were derived from 4-chloro/phenoxy-phenols, triclosan, quinolin-8-ol, naphthols and terpene alcohols. The experiments identified enoyl-acyl carrier protein reductase (InhA), and thus mycobacterial cell wall biosynthesis, as the main target of the molecules that are activated by KatG, but for some compounds can also be expected adjunctive mechanism(s). Generally, the mutual esters have also avoided cytotoxicity and are promising hits for the discovery of antimycobacterial drugs with improved properties compared to parent isoniazid.