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

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

  • Eur J Med Chem. 2022 Jul 5;237:114404. doi: 10.1016/j.ejmech.2022.114404.
Dorothy Semenya 1,  Meir Touitou 1,  Domiziana Masci 1,  Camila Maringolo Ribeiro 2,  Fernando Rogerio Pavan 2,  Guilherme Felipe Dos Santos Fernandes 1,  Beatrice Gianibbi 3,  Fabrizio Manetti 3,  Daniele Castagnolo 4
Affiliations

Affiliations

  • 1 School of Cancer and Pharmaceutical Sciences, King's College London, 150 Stamford Street, SE1 9NH, London, United Kingdom.
  • 2 Tuberculosis Research Laboratory, School of Pharmaceutical Sciences, Sao Paulo State University (UNESP), Rod. Araraquara-Jau, km1, 14800-903, Araraquara, Brazil.
  • 3 Dipartimento di Biotecnologie, Chimica e Farmacia, Dipartimento di Eccellenza 2018-2022, University of Siena, via A. Moro 2, I-53100, Siena, Italy.
  • 4 School of Cancer and Pharmaceutical Sciences, King's College London, 150 Stamford Street, SE1 9NH, London, United Kingdom. Electronic address: d.castagnolo@ucl.ac.uk.
PMID: 35486992 DOI: 10.1016/j.ejmech.2022.114404
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.

Keywords

Antimicrobial resistance; Antimycobacterial; MDR-TB; Pyrrole; SAR; Tuberculosis.

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