Pomel S, Dubar F, Forge D, Loiseau P M, Biot C
Univ. Paris-Sud, Faculté de Pharmacie, UMR 8076 CNRS, Chimiothérapie Antiparasitaire, 92290 Châtenay-Malabry, France.
Univ. Lille 1, UGSF, UMR 8576 CNRS, 59650 Villeneuve d'Ascq, France.
Bioorg Med Chem. 2015 Aug 15;23(16):5168-74. doi: 10.1016/j.bmc.2015.03.029. Epub 2015 Mar 20.
Three new series of quinoline, quinolone, and benzimidazole derivatives were synthesized and evaluated in vitro against Trypanosoma brucei gambiense. In the quinoline series, the metallo antimalarial drug candidate (ferroquine, FQ) and its ruthenium analogue (ruthenoquine, RQ, compound 13) showed the highest in vitro activities with IC50 values around 0.1 μM. Unfortunately, both compounds failed to cure Trypanosoma brucei brucei infected mice in vivo. The other heterocyclic compounds were active in vitro with IC50 values varying from 0.8 to 34 μM. One of the most interesting results was a fluoroquinolone derivative (compound 2) that was able to offer a survival time of 8 days after a treatment at the single dose of 100 μmol/kg by intraperitoneal route. Although no clear-cut structure-activity relationships emerged, further pharmacomodulations are worth to be developed in this series.
合成了三个新系列的喹啉、喹诺酮和苯并咪唑衍生物，并对其进行体外抗布氏冈比亚锥虫活性评估。在喹啉系列中，金属抗疟候选药物（铁喹啉，FQ）及其钌类似物（钌喹啉，RQ，化合物13）表现出最高的体外活性，IC50值约为0.1μM。遗憾的是，这两种化合物均未能在体内治愈感染布氏布氏锥虫的小鼠。其他杂环化合物在体外具有活性，IC50值在0.8至34μM之间变化。最有趣的结果之一是一种氟喹诺酮衍生物（化合物2），通过腹腔途径以100μmol/kg的单剂量给药后，能够提供8天的存活时间。尽管没有出现明确的构效关系，但该系列仍值得进一步开展药效学调制研究。
