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Structural Rigidification of N-Aryl-pyrroles into Indoles Active against Intracellular and Drug-Resistant Mycobacteria

Research output: Contribution to journalArticlepeer-review

Dorothy Semenya, Meir Touitou, Camila Maringolo Ribeiro, Fernando Rogerio Pavan, Luca Pisano, Vinayak Singh, Kelly Chibale, Georg Bano, Anita Toscani, Fabrizio Manetti, Beatrice Gianibbi, Daniele Castagnolo

Original languageEnglish
JournalAcs Medicinal Chemistry Letters
Issue number1
Early online date8 Dec 2021
Accepted/In press2021
E-pub ahead of print8 Dec 2021

Bibliographical note

Funding Information: We gratefully acknowledge EPSRC (Global Challenges Competition King’s College London). D.S. acknowledges the South African National Research Foundation-SARChI for financial support. M.T. acknowledges King’s College London for a period of leave. D.C. and A.T. acknowledge the University of London for the Maplethorpe Fellowship to A.T.. The South African Medical Research Council (SAMRC), the South African Department of Science and Innovation, and the South African National Research Foundation are gratefully acknowledged for research funding (K.C. and V.S.). F.R.P. acknowledges São Paulo Research Foundation (FAPESP) for financial support. Publisher Copyright: © 2021 American Chemical Society.

King's Authors


A series of indolyl-3-methyleneamines incorporating lipophilic side chains were designed through a structural rigidification approach and synthesized for investigation as new chemical entities against Mycobacterium tuberculosis (Mtb). The screening led to the identification of a 6-chloroindole analogue 7j bearing an N-octyl chain and a cycloheptyl moiety, which displayed potent in vitro activity against laboratory and clinical Mtb strains, including a pre-extensively drug-resistant (pre-XDR) isolate. 7j also demonstrated a marked ability to restrict the intracellular growth of Mtb in murine macrophages. Further assays geared toward mechanism of action elucidation have thus far ruled out the involvement of various known promiscuous targets, thereby suggesting that the new indole 7j may inhibit Mtb via a unique mechanism.

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