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

doi:10.1021/jm4012774

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 journal › Article › peer-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 language	English (US)
Pages (from-to)	8849-8859
Number of pages	11
Journal	Journal of Medicinal Chemistry
Volume	56
Issue number	21
DOIs	https://doi.org/10.1021/jm4012774
State	Published - Nov 14 2013
Externally published	Yes

All Science Journal Classification (ASJC) codes

Molecular Medicine
Drug Discovery

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Kondreddi, R. R., Jiricek, J., Rao, S. P. S., Lakshminarayana, S. B., Camacho, L. R., Rao, R., Herve, M., Bifani, P., Ma, N. L., Kuhen, K., Goh, A., Chatterjee, A. K., Dick, T., Diagana, T. T., Manjunatha, U. H., & Smith, P. W. (2013). Design, synthesis, and biological evaluation of indole-2-carboxamides: A promising class of antituberculosis agents. Journal of Medicinal Chemistry, 56(21), 8849-8859. https://doi.org/10.1021/jm4012774

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. / Design, synthesis, and biological evaluation of indole-2-carboxamides : A promising class of antituberculosis agents. In: Journal of Medicinal Chemistry. 2013 ; Vol. 56, No. 21. pp. 8849-8859.

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

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.",

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

year = "2013",

month = nov,

day = "14",

doi = "10.1021/jm4012774",

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Kondreddi, RR, Jiricek, J, Rao, SPS, Lakshminarayana, SB, Camacho, LR, Rao, R, Herve, M, Bifani, P, Ma, NL, Kuhen, K, Goh, A, Chatterjee, AK, Dick, T, Diagana, TT, Manjunatha, UH & Smith, PW 2013, 'Design, synthesis, and biological evaluation of indole-2-carboxamides: A promising class of antituberculosis agents', Journal of Medicinal Chemistry, vol. 56, no. 21, pp. 8849-8859. https://doi.org/10.1021/jm4012774

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

In: Journal of Medicinal Chemistry, Vol. 56, No. 21, 14.11.2013, p. 8849-8859.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Design, synthesis, and biological evaluation of indole-2-carboxamides

T2 - A promising class of antituberculosis agents

AU - Kondreddi, Ravinder Reddy

AU - Jiricek, Jan

AU - Rao, Srinivasa P S

AU - Lakshminarayana, Suresh B.

AU - Camacho, Luis R.

AU - Rao, Ranga

AU - Herve, Maxime

AU - Bifani, Pablo

AU - Ma, Ngai Ling

AU - Kuhen, Kelli

AU - Goh, Anne

AU - Chatterjee, Arnab K.

AU - Dick, Thomas

AU - Diagana, Thierry T.

AU - Manjunatha, Ujjini H.

AU - Smith, Paul W.

PY - 2013/11/14

Y1 - 2013/11/14

N2 - 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.

AB - 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.

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