Infections Parasitaires, Transmission, Physiopathologie et Thérapeutique, UMR MD3, Faculté de Pharmacie, Aix-Marseille Université, 27 Boulevard Jean Moulin, CS 30064, 13385 Marseille cedex 05, France.
Eur J Med Chem. 2012 Aug;54:75-86. doi: 10.1016/j.ejmech.2012.04.029. Epub 2012 May 2.
A series of nitrated 2-substituted-quinolines was synthesized and evaluated in vitro toward Leishmania donovani promastigotes. In parallel, the in vitro cytotoxicity of these molecules was assessed on the murine J774 and human HepG2 cell lines. Thus, a very promising antileishmanial hit molecule was identified (compound 21), displaying an IC(50) value of 6.6 μM and CC(50) values ≥ 100 μM, conferring quite good selectivity index to this molecule, in comparison with 3 drug-compounds of reference (amphotericin B, miltefosine and pentamidine). Compound 21 also appears as an efficient in vitro antileishmanial molecule against both Leishmania infantum promastigotes and the intracellular L. donovani amastigotes (respective IC(50) = 7.6 and 6.5 μM). Moreover, hit quinoline 21 does not show neither significant antiplasmodial nor antitoxoplasmic in vitro activity and though, presents a selective antileishmanial activity. Finally, a structure-activity relationships study enabled to define precisely the antileishmanial pharmacophore based on this nitroquinoline scaffold: 2-hydroxy-8-nitroquinoline.
合成了一系列硝代 2-取代喹啉，并对其进行了体外评估，以研究其对利什曼原虫前鞭毛体的作用。同时，在体外评估了这些分子对小鼠 J774 和人 HepG2 细胞系的细胞毒性。因此，确定了一种非常有前景的抗利什曼原虫的有效分子（化合物 21），其 IC50 值为 6.6 μM，CC50 值≥100 μM，与 3 种参考药物（两性霉素 B、米替福新和喷他脒）相比，该分子的选择性指数相当好。化合物 21 对利什曼原虫婴儿前鞭毛体和细胞内利什曼原虫无鞭毛体也表现出有效的体外抗利什曼原虫作用（相应的 IC50 值分别为 7.6 和 6.5 μM）。此外，该有效喹啉 21 既没有表现出明显的抗疟原虫活性，也没有表现出抗弓形虫活性，而是表现出选择性的抗利什曼原虫活性。最后，通过构效关系研究，基于该硝基喹啉支架确定了抗利什曼原虫的药效团：2-羟基-8-硝基喹啉。
