Tapping into the antitubercular potential of 2,5-dimethylpyrroles: A structure-activity relationship interrogation

Author(s)

Semenya, Dorothy ; Touitou, Meir ; Masci, Domiziana ; Ribeiro, Camila Maringolo ; Pavan, Fernando Rogerio ; Fernandes, Guilherme Felipe Dos Santos ; Gianibbi, Beatrice ; Manetti, Fabrizio ; Castagnolo, Daniele

• Document type: Journal article
• Source: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY; v. 237, p. 15-pg., 2022-04-26.

Abstract

An exploration of the chemical space around a 2,5-dimethylpyrrole scaffold of antitubercular hit compound 1 has led to the identification of new derivatives active against Mycobacterium tuberculosis and multidrug-resistant clinical isolates. Analogues incorporating a cyclohexanemethyl group on the methyleneamine side chain at C3 of the pyrrole core, including 5n and 5q, exhibited potent inhibitory effects against the M. tuberculosis strains, substantiating the essentiality of the moiety to their antimycobacterial activity. In addition, selected derivatives showed promising cytotoxicity profiles against human pulmonary fibroblasts and/or murine macrophages, proved to be effective in inhibiting the growth of intracellular mycobacteria, and elicited either bactericidal effects, or bacteriostatic activity comparable to 1. Computational studies revealed that the new compounds bind to the putative target, MmpL3, in a manner similar to that of known inhibitors BM212 and SQ109. (AU)

• FAPESP's process: 20/13497-4 - Search for the mechanism of action and therapeutic effect of new classes of drugs against Mycobacterium tuberculosis
• Grantee: Fernando Rogério Pavan
• Support Opportunities: Regular Research Grants