Kondreddi, Ravinder Reddy, Jiricek, Jan, Rao, Srinivasa P.S., Lakshminarayana, Suresh Bangalore, Rao, Ranga Rao K.R., Herve, Maxime Marcel, Bifani, Juan Pablo, Kuhen, Kelli, Manjunatha, Ujjini Havaldar, Smith, Paul William, Camacho, Luis, Ma, Ida, Goh, Anne and Chatterjee, Arnab (2013) Design, synthesis and biological evaluation of indole-2-carboxamides, a promising class of anti-tuberculosis agents. J. med Chem, 56. pp. 8849-8859.

Abstract

Indole-2-carboxamides have been identified as a promising class of anti-tuberculosis agents from phenotypic whole cell high-throughput screening against mycobacteria. One of the hits KCD644, an N-cyclohexyl-4,6-dimethyl-1H-indole-2-carboxamide had low µM potency, high in vitro mouse liver microsomal clearance and low aqueous solubility. Structure activity relationship studies revealed that attaching further small alkyl groups to the cyclohexyl ring significantly improved activity against Mycobacterium tuberculosis (Mtb) but reduced aq solubility. Further, chloro, fluoro or cyano substitutions on the 4- and 6-positions of the indole ring and mono or dimethyl substitution on the 4-position of the cyclohexyl ring significantly improved both in vitro and in vivo metabolic stability. KDZ304 and KDZ349, the lead candidates from this study displayed improved in vitro activity compared to the current standard TB drugs. The low aq solubility of compounds in the series could not be mitigated due to the correlation of lipophilicity with potency against Mtb. However, both compounds displayed favorable in vivo pharmacokinetic properties in rodents when dosed in a microemulsion preconcentrate formulation (MEPC). Both KDZ304 and KDZ349 delivered good oral exposure and also demonstrated in vivo efficacy in a mouse model. Thus, indole-2-carboxamides represent a promising new class of anti-TB agents.

Item Type:	Article
Date Deposited:	13 Oct 2015 13:13
Last Modified:	13 Oct 2015 13:13
URI:	https://oak.novartis.com/id/eprint/10624