Identification of a diverse indole-2-carboxamides as a potent antileishmanial chemotypes

Eur J Med Chem. 2016 Mar 3:110:237-45. doi: 10.1016/j.ejmech.2016.01.028.

Shashi Pandey ¹, Shikha S Chauhan ¹, Rahul Shivahare ², Abhisheak Sharma ³, Swati Jaiswal ³, Suman Gupta ², Jawahar Lal ³, Prem M S Chauhan ⁴

Affiliations

1 Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, Lucknow 226031, U.P., India.
2 Division of Parasitology, CSIR-Central Drug Research Institute, Lucknow 226031, U.P., India.
3 Pharmacokinetics & Metabolism Division, CSIR-Central Drug Research Institute, Lucknow 226031, U.P., India; Academy of Scientific and Innovative Research, New Delhi, India.
4 Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, Lucknow 226031, U.P., India. Electronic address: prem_chauhan_2000@yahoo.com.

PMID: 26840364 DOI: 10.1016/j.ejmech.2016.01.028

Abstract

A novel series of highly diverse indole-2-carboxamides was synthesized utilizing the isocyanide based multicomponent reaction (IMCR)-post modification approach and were identified as potential antileishmanial chemotype. Among the synthesized 18 analogues, 12 analogues exhibited better antileishmanial activity against intracellular amastigotes form of Leishmania donovani (IC50 values of 0.6-7.5 μM) as compared to standard drugs miltefosine and sodium stibogluconate. The compounds were also non-toxic towards Vero cells. Compounds 2b, 2m and 2p with significant in vitro activity were then evaluated for their in vivo efficacy following intraperitoneal route. These three compounds at a concentration of 50 mg/kg/day for 5 consecutive days showed 70.0, 63.5 and 63.4% inhibition of Leishmania amastigotes, respectively at day 7 post treatment in hamster model of visceral leishmaniasis.

Keywords

Hamster model; Indole-2-carboxamide; Leishmania donovani; Multicomponent reaction.

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