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

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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)

Abstract

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.

Original languageEnglish
JournalAcs Medicinal Chemistry Letters
Volume13
Issue number1
Early online date8 Dec 2021
DOIs
Publication statusE-pub ahead of print - 8 Dec 2021

Keywords

  • Antimicrobial resistance
  • Indole
  • MDR-TB
  • Pyrrole
  • Tuberculosis
  • XDR-TB

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