An antikinetoplastid pharmacomodulation study at position 3 of the recently described hit molecule 3‐bromo‐8‐nitroquinolin‐2(1H)‐one was conducted. Twenty‐four derivatives were synthesised using the Suzuki–Miyaura cross‐coupling reaction and evaluated in vitro on both Leishmania infantum axenic amastigotes and Trypanosoma brucei brucei trypomastigotes. Introduction of a para‐carboxyphenyl group at position 3 of the scaffold led to the selective antitrypanosomal hit molecule 3‐(4‐carboxyphenyl)‐8‐nitroquinolin‐2(1H)‐one (21) with a lower reduction potential (−0.56 V) than the initial hit (−0.45 V). Compound 21 displays micromolar antitrypanosomal activity (IC₅₀=1.5 μm) and low cytotoxicity on the human HepG2 cell line (CC₅₀=120 μm), having a higher selectivity index (SI=80) than the reference drug eflornithine. Contrary to results previously obtained in this series, hit compound 21 is inactive toward L. infantum and is not efficiently bioactivated by T. brucei brucei type I nitroreductase, which suggests the existence of an alternative mechanism of action.

中文翻译：

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使用钯催化的交叉偶联反应对 8-硝基喹啉-2(1H)-one 支架的位置 3 进行抗锥虫药物调节

对最近描述的命中分子 3-bromo-8-硝基喹啉-2(1 H )-one 的位置 3 进行了抗动质体药物调节研究。使用 Suzuki-Miyaura 交叉偶联反应合成了 24 种衍生物，并在婴儿利什曼原虫无菌无鞭毛体和布氏锥虫锥鞭毛体上进行了体外评估。在支架的3位引入对羧基苯基导致选择性抗锥虫命中分子3-(4-羧基苯基)-8-硝基喹啉-2(1 H )-酮( 21 )具有较低的还原电位(-0.56 V) 比初始击中 (−0.45 V) 更高。化合物21对人HepG2细胞系表现出微摩尔抗锥虫活性(IC ₅₀ =1.5μm )和低细胞毒性(CC ₅₀ =120μm )，具有比参比药物依氟鸟氨酸更高的选择性指数(SI=80 ) 。与本系列之前获得的结果相反，命中化合物21对婴儿乳杆菌没有活性，并且不能被婴儿乳杆菌有效地生物激活。 brucei brucei I 型硝基还原酶，这表明存在替代作用机制。