Semenya, Dorothy;
Touitou, Meir;
Masci, Domiziana;
Ribeiro, Camila Maringolo;
Pavan, Fernando Rogerio;
Dos Santos Fernandes, Guilherme Felipe;
Gianibbi, Beatrice;
... Castagnolo, Daniele; + view all
(2022)
Tapping into the antitubercular potential of 2,5-dimethylpyrroles: A structure-activity relationship interrogation.
European Journal of Medicinal Chemistry
, 237
, Article 114404. 10.1016/j.ejmech.2022.114404.
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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.
| Type: | Article |
|---|---|
| Title: | Tapping into the antitubercular potential of 2,5-dimethylpyrroles: A structure-activity relationship interrogation |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1016/j.ejmech.2022.114404 |
| Publisher version: | https://doi.org/10.1016/j.ejmech.2022.114404 |
| Language: | English |
| Additional information: | This version is the author accepted manuscript. For information on re-use, please refer to the publisher's terms and conditions. |
| Keywords: | Tuberculosis, Antimicrobial resistance, Antimycobacterial, MDR-TB, Pyrrole, SAR |
| UCL classification: | UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences > Dept of Chemistry UCL > Provost and Vice Provost Offices > UCL BEAMS UCL |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10147995 |
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