Design, Synthesis, and Biological Evaluation of Indole-2-carboxamides: A Promising Class of Antituberculosis Agents

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...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2013-11, Vol.56 (21), p.8849-8859
Main Authors: Kondreddi, Ravinder Reddy, Jiricek, Jan, Rao, Srinivasa P. S, Lakshminarayana, Suresh B, Camacho, Luis R, Rao, Ranga, Herve, Maxime, Bifani, Pablo, Ma, Ngai Ling, Kuhen, Kelli, Goh, Anne, Chatterjee, Arnab K, Dick, Thomas, Diagana, Thierry T, Manjunatha, Ujjini H, Smith, Paul W
Format: Article
Language:English
Subjects:
Animals
Antitubercular Agents - chemical synthesis
Antitubercular Agents - chemistry
Antitubercular Agents - pharmacology
Dose-Response Relationship, Drug
Drug Design
Humans
Indoles - chemical synthesis
Indoles - chemistry
Indoles - pharmacology
Mice
Microbial Sensitivity Tests
Microsomes, Liver - chemistry
Microsomes, Liver - metabolism
Molecular Structure
Mycobacterium tuberculosis - drug effects
Rats
Solubility
Structure-Activity Relationship
Tuberculosis - drug therapy
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Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm4012774