Design and synthesis of 2-(2-isonicotinoylhydrazineylidene) propanamides as InhA inhibitors with high antitubercular activity

Based on successful antitubercular isoniazid scaffold we have designed its mee-too analogues by a combination of this drug linked with substituted anilines through pyruvic acid as a bridge. Lipophilicity important for passive diffusion through impenetrable mycobacterial cell wall was increased by halogen substitution on the aniline. We prepared twenty new 2-(2-isonicotinoylhydrazineylidene)propanamides that were assayed against susceptible Mycobacterium tuberculosis H(37)Rv, nontuberculous mycobacteria, and also multidrug-resistant tuberculous strains (MDR-TB). All the compounds showed excellent activity not only against Mtb. (minimum inhibitory concentrations, MIC, from <= 0.03 mu M), but also against M. kansasii (MIC >= 2 mu M). The most active molecules have CF3 and OCF3 substituent in the position 4 on the aniline ring. MIC against MDR-TB were from 8 mu M. The most effective derivatives were used for the mechanism of action investigation. The treatment of Mtb. H37Ra with tested compounds led to decreased production of mycolic acids and the strains overproducing InhA were more resistant to them. These results confirm that studied compounds inhibit the enoyl-acyl carrier protein reductase (InhA) in mycobacteria. The compounds did not show any cytotoxic and cytostatic activity for HepG2 cells. The amides can be considered as a promising scaffold for antitubercular drug discovery having better anti-microbial properties than original isoniazid together with a significantly improved pharmaco-toxicological profile. (C) 2021 Elsevier Masson SAS. All rights reserved.

Automated summary

Novel compounds based on isoniazid scaffold were designed and synthesized with increased lipophilicity for improved antitubercular activity. The compounds exhibited excellent activity against susceptible and resistant strains of Mycobacterium tuberculosis, potentially inhibiting enoyl-acyl carrier protein reductase and showing promising prospects for drug discovery in tuberculosis treatment.