Targeting the human parasite Leishmania donovani: discovery of a new promising anti-infectious pharmacophore in 3-nitroimidazo[1,2-a]pyridine series.
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 μM) 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.
Equipe Pharmacochimie Radicalaire, Faculté de Pharmacie, Aix-Marseille Université - UMR CNRS 7273, Institut de Chimie Radicalaire, 27 Boulevard Jean Moulin-CS30064, 13385 Marseille Cedex 05, France.
Caroline
C
Castera-Ducros
Lucie
L
Paloque
Pierre
P
Verhaeghe
Magali
M
Casanova
Christophe
C
Cantelli
Sébastien
S
Hutter
Floriane
F
Tanguy
Michèle
M
Laget
Vincent
V
Remusat
Anita
A
Cohen
Maxime D
MD
Crozet
Pascal
P
Rathelot
Nadine
N
Azas
Patrice
P
Vanelle
D000818:Animals; D000981:Antiprotozoal Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D056945:Hep G2 Cells; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D007893:Leishmania donovani / Q000187:drug effects*; D051379:Mice; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D013329:Structure-Activity Relationship
D000981:Antiprotozoal Agents; D007093:Imidazoles; D011725:Pyridines; C001439:imidazo(1,2-a)pyridine
HepG2 in vitro cytotoxicity; Imidazo[1,2-a]pyridine; Leishmania donovani; Structure–activity relationships