TY - JOUR
T1 - Tapping into the antitubercular potential of 2,5-dimethylpyrroles
T2 - A structure-activity relationship interrogation
AU - Semenya, Dorothy
AU - Touitou, Meir
AU - Masci, Domiziana
AU - Ribeiro, Camila Maringolo
AU - Pavan, Fernando Rogerio
AU - Dos Santos Fernandes, Guilherme Felipe
AU - Gianibbi, Beatrice
AU - Manetti, Fabrizio
AU - Castagnolo, Daniele
N1 - 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
PY - 2022/7/5
Y1 - 2022/7/5
N2 - 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.
AB - 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.
KW - Antimicrobial resistance
KW - Antimycobacterial
KW - MDR-TB
KW - Pyrrole
KW - SAR
KW - Tuberculosis
UR - http://www.scopus.com/inward/record.url?scp=85129861578&partnerID=8YFLogxK
U2 - 10.1016/j.ejmech.2022.114404
DO - 10.1016/j.ejmech.2022.114404
M3 - Article
C2 - 35486992
AN - SCOPUS:85129861578
SN - 0223-5234
VL - 237
JO - EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
JF - EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
M1 - 114404
ER -
