Design, synthesis, and biological evaluation of indole-2-carboxamides: A promising class of antituberculosis agents

Ravinder Reddy Kondreddi, Jan Jiricek, Srinivasa P S Rao, Suresh B. Lakshminarayana, Luis R. Camacho, Ranga Rao, Maxime Herve, Pablo Bifani, Ngai Ling Ma, Kelli Kuhen, Anne Goh, Arnab K. Chatterjee, Thomas Dick, Thierry T. Diagana, Ujjini H. Manjunatha, Paul W. Smith

Research output: Contribution to journalArticlepeer-review

60 Scopus citations

Abstract

Indole-2-carboxamides have been identified as a promising class of antituberculosis agents from phenotypic screening against mycobacteria. One of the hits, indole-2-carboxamide analog (1), had low micromolar potency against Mycobacterium tuberculosis (Mtb), high mouse liver microsomal clearance, and low aqueous solubility. Structure-activity relationship studies revealed that attaching alkyl groups to the cyclohexyl ring significantly improved Mtb activity but reduced solubility. Furthermore, chloro, fluoro, or cyano substitutions on the 4- and 6-positions of the indole ring as well as methyl substitution on the cyclohexyl ring significantly improved metabolic stability. 39 and 41, the lead candidates, displayed improved in vitro activity compared to most of the current standard TB drugs. The low aqueous solubility could not be mitigated because of the positive correlation of lipophilicity with Mtb potency. However, both compounds displayed favorable oral pharmacokinetic properties in rodents and demonstrated in vivo efficacy. Thus, indole-2-carboxamides represent a promising new class of antituberculosis agents.

Original languageEnglish (US)
Pages (from-to)8849-8859
Number of pages11
JournalJournal of Medicinal Chemistry
Volume56
Issue number21
DOIs
StatePublished - Nov 14 2013
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

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