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

Autor(es)

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

• Tipo de documento: Artigo Científico
• Fonte: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY; v. 237, p. 15-pg., 2022-04-26.

Resumo

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)

• Processo FAPESP: 20/13497-4 - Busca do mecanismo de ação e efeito terapêutico de novas classes de fármacos contra Mycobacterium tuberculosis
• Beneficiário: Fernando Rogério Pavan
• Modalidade de apoio: Auxílio à Pesquisa - Regular