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Antimicrob Agents Chemother. 2014 Sep;58(9):5325-31. doi: 10.1128/AAC.03233-14. Epub 2014 Jun 23.

1,4-azaindole, a potential drug candidate for treatment of tuberculosis.

Author information

1
Department of Biosciences, IMED Infection, AstraZeneca, Bangalore, India monalisa.chatterji@gmail.com radha.shandil@astrazeneca.com psshirude@gmail.com.
2
DMPK and Animal Sciences, IMED Infection, AstraZeneca, Bangalore, India monalisa.chatterji@gmail.com radha.shandil@astrazeneca.com psshirude@gmail.com.
3
Department of Medicinal Chemistry, IMED Infection, AstraZeneca, Bangalore, India.
4
DMPK and Animal Sciences, IMED Infection, AstraZeneca, Bangalore, India.
5
Department of Biosciences, IMED Infection, AstraZeneca, Bangalore, India.
6
Safety Assessment, IMED, AstraZeneca, Alderly Park, Mereside, United Kingdom.
7
Global Alliance for TB Drug Development, New York, New York, USA.
8
Department of Medicinal Chemistry, IMED Infection, AstraZeneca, Bangalore, India monalisa.chatterji@gmail.com radha.shandil@astrazeneca.com psshirude@gmail.com.

Abstract

New therapeutic strategies against multidrug-resistant (MDR) and extensively drug-resistant (XDR) Mycobacterium tuberculosis are urgently required to combat the global tuberculosis (TB) threat. Toward this end, we previously reported the identification of 1,4-azaindoles, a promising class of compounds with potent antitubercular activity through noncovalent inhibition of decaprenylphosphoryl-β-D-ribose 2'-epimerase (DprE1). Further, this series was optimized to improve its physicochemical properties and pharmacokinetics in mice. Here, we describe the short-listing of a potential clinical candidate, compound 2, that has potent cellular activity, drug-like properties, efficacy in mouse and rat chronic TB infection models, and minimal in vitro safety risks. We also demonstrate that the compounds, including compound 2, have no antagonistic activity with other anti-TB drugs. Moreover, compound 2 shows synergy with PA824 and TMC207 in vitro, and the synergy effect is translated in vivo with TMC207. The series is predicted to have a low clearance in humans, and the predicted human dose for compound 2 is ≤1 g/day. Altogether, our data suggest that a 1,4-azaindole (compound 2) is a promising candidate for the development of a novel anti-TB drug.

PMID:
24957839
PMCID:
PMC4135869
DOI:
10.1128/AAC.03233-14
[Indexed for MEDLINE]
Free PMC Article

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