Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 21, Issue 22, Pages 7155-7164Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2013.09.002
Keywords
Leishmania donovani; Imidazo[1,2-a]pyridine; Structure-activity relationships; HepG2 in vitro cytotoxicity
Funding
- Centre National de la Recherche Scientifique (CNRS)
- Aix-Marseille Universite
- Region PACA/Yelen BDE Grant
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We report herein the discovery of antileishmanial molecules based on the imidazo[1,2-a]pyridine ring. In vitro screenings of imidazopyridines belonging to our chemical library, toward the promastigotes stage of Leishmania donovani, J774A. 1 murine and HepG2 human cells, permitted to identify three selective hit-compounds (12, 20 and 28). New derivatives were then synthesized to allow structure-activity and -toxicity relationships analyses, enabling to characterize a lead-compound (44) displaying both a high potency (IC50 = 1.8 mu M) and a good selectivity index, in comparison with three antileishmanial reference drug-compounds (amphotericin B, miltefosine and pentamidine). Moreover, lead-compound 44 also exhibits good in vitro activity against the intracellular amastigote stage of L. donovani. Thus, the 6-halo-3-nitro-2-(phenylsulfonylmethyl)imidazo[1,2-a]pyridine scaffold appears as a new promising selective antileishmanial pharmacophore, especially when substituted at position 8 by a bromine atom. (C) 2013 Elsevier Ltd. All rights reserved.
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