Abstract

Background: Previously, modification of isoniazide- and pyrazinamide-derived pharmacophores via the Ugi multicomponent reaction proved to be an effective strategy to obtain efficacious and non-cytotoxic antimycobacterial leads.

Objective: To apply the hydrazino-Ugi reaction developed in our group toward modifying these pharmacophores with similar appendages as reported previously; to create hydrolytically more stable compounds which are based on acyl hydrazine, rather than diamide backbone.

Method: Six hydrazino-Ugi products were synthesized and modified at the reactive nitrogen atom via reductive alkylation. Additionally, by conducting the hydrazino-Ugi reaction in methanol, three methyl ester by-products were obtained and tested alongside the main library. Compounds were screened against M. tuberculosis H37Rv strain and checked for cytotoxicity vs. HEK293 cells. Hydrolytic stability of a model Ugi and one of the newly synthesized hydrazino-Ugi products was compared in rat plasma stability experiments.

Results: 6 out of 20 compounds prepared and tested, displayed potent inhibition of M. tuberculosis growth and virtually no cytotoxicity in the testing concentration range. The stability of a sample hydrazino-Ugi product in rat plasma was over 3 times higher compared to that of one of the Ugi products reported earlier.

Conclusion: Hydrazino-Ugi reaction represents an effective way to modify classical antitubercular chemotypes and generate compounds endowed with specific antimycobacterial activity. These are new, hydrolytically stable leads for the future antitubercular therapy development.

Keywords: Isoniazid, pyrazinamide, hydrazino-Ugi reaction, isocyanide-based multicomponent reactions, antitubercular chemotherapy, therapeutic window.

Graphical Abstract