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

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

Original languageEnglish
Article number114404
Published5 Jul 2022

Bibliographical note

Funding Information: DS acknowledges the South African National Research Foundation-SARChI for financial support. DM acknowledges the University of Rome “La Sapienza” for Mobility Projects Call for Research Doctorates (n. 2682). European Union's Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement (No 101027065) is acknowledged for support to GFDSF. FRP acknowledges Fundação de Amparo à Pesquisa do Estado de São Paulo ( FAPESP ) for financial support (grant 2020/13497-4 ). Support from the Italian Ministry of University and Research ("Dipartimenti di Eccellenza" Program, 2018-2022) to Department of Biotechnology, Chemistry and Pharmacy (University of Siena), is also acknowledged. Publisher Copyright: © 2022 Elsevier Masson SAS

King's Authors


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.

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