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.
Bioorg Med Chem. 2013 Nov 15;21(22):7155-64. doi: 10.1016/j.bmc.2013.09.002. Epub 2013 Sep 11.
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.
我们在此报告了基于咪唑并[1,2-a]吡啶环的抗利什曼原虫分子的发现。对属于我们化学文库的咪唑并吡啶进行体外筛选，针对利什曼原虫、J774A.1 鼠和 HepG2 人细胞的前体阶段，鉴定出三种选择性命中化合物（12、20 和 28）。然后合成了新的衍生物，以允许进行结构-活性和毒性关系分析，从而表征出一种先导化合物（44），与三种抗利什曼原虫的参考药物化合物（两性霉素 B、米替福新和喷他脒）相比，具有高活性（IC50=1.8 μM）和良好的选择性指数。此外，先导化合物 44 对利什曼原虫的细胞内无鞭毛体阶段也表现出良好的体外活性。因此，6-卤代-3-硝基-2-（苯磺酰甲基）咪唑并[1,2-a]吡啶支架似乎是一种新的有前途的选择性抗利什曼原虫药效团，特别是当 8 位被溴原子取代时。
