Centre of Excellence for Pharmaceutical Sciences, North-West University, Potchefstroom, 2520, South Africa.
National Research Center for Protozoan Diseases, Obihiro University of Agriculture and Veterinary Medicine, Inada, Obihiro, Hokkaido, 080-8555, Japan.
Mol Divers. 2024 Aug;28(4):2667-2680. doi: 10.1007/s11030-023-10704-9. Epub 2023 Jul 23.
Tropical diseases, such as African trypanosomiasis, by their nature and prevalence lack the necessary urgency regarding drug development, despite the increasing need for novel, structurally diverse antitrypanosomal drugs, using different mechanisms of action that would improve drug efficacy and safety. Traditionally antibacterial agents, the fluoroquinolones, reportedly possess in vitro trypanocidal activities against Trypanosoma brucei organisms. During our research, the fluroquinolone, ciprofloxacin (1), and its analogs (2-24) were tested against bloodstream forms of T. brucei brucei, T. b. gambiense, T. b. rhodesiense, T. evansi, T. equiperdum, and T. congolense and Madin-Darby bovine kidney cells (cytotoxicity). Ciprofloxacin [CPX (1)] demonstrated selective trypanocidal activity against T. congolense (IC 7.79 µM; SI 39.6), whereas the CPX derivatives (2-10) showed weak selective activity (25 < IC < 65 µM; 2 < SI < 4). Selectivity and activity of the CPX and 1,2,3-triazole (TZ) hybrids (11-24) were governed by their chemical functionality at C-3 (carboxylic acid, or 4-methylpiperazinyl amide) and their electronic effect (electron-donating or electron-withdrawing para-benzyl substituent), respectively. Trypanocidal hits in the micromolar range were identified against bloodstream forms of T. congolense [CPX (1); CPX amide derivatives 18: IC 8.95 µM; SI 16.84; 22: IC 5.42 µM; SI 25.2] and against T. brucei rhodesiense (CPX acid derivative 13: IC 4.51 µM; SI 10.2), demonstrating more selectivity toward trypanosomes than mammalian cells. Hence, the trypanocidal hit compound 22 may be optimized by retaining the 4-methylpiperazine amide functional group (C-3) and the TZ moiety at position N-15 and introducing other electron-withdrawing ortho-, meta-, and/or para-substituents on the aryl ring in an effort to improve the pharmacokinetic properties and increase the trypanocidal activity.
热带病，如非洲锥虫病，由于其性质和流行程度，在开发药物方面缺乏必要的紧迫性，尽管人们越来越需要新型的、结构多样的抗锥虫药物，这些药物采用不同的作用机制，将提高药物的疗效和安全性。传统的抗菌药物，氟喹诺酮类药物，据称对布氏锥虫生物体具有体外杀锥虫活性。在我们的研究中，氟喹诺酮类药物环丙沙星（1）及其类似物（2-24）被测试了对布氏锥虫布鲁斯、布氏锥虫冈比亚、布氏锥虫罗得西亚、伊氏锥虫、伊氏锥虫驴、刚果锥虫和马迪丹-达比牛肾细胞（细胞毒性）的血液形式。环丙沙星[CPX（1）]对刚果锥虫具有选择性杀锥虫活性（IC 7.79 µM；SI 39.6），而 CPX 衍生物（2-10）则显示出较弱的选择性活性（25 < IC < 65 µM；2 < SI < 4）。CPX 和 1,2,3-三唑（TZ）杂合体（11-24）的选择性和活性由其在 C-3 位的化学官能团（羧酸或 4-甲基哌嗪基酰胺）和电子效应（供电子或吸电子的对位苄基取代基）决定。在微摩尔范围内对刚果锥虫血液形式具有杀锥虫作用的化合物被鉴定为环丙沙星（1）；CPX 酰胺衍生物 18：IC 8.95 µM；SI 16.84；22：IC 5.42 µM；SI 25.2]和罗得西亚锥虫（CPX 酸衍生物 13：IC 4.51 µM；SI 10.2），对哺乳动物细胞的选择性高于锥虫。因此，杀锥虫化合物 22 可以通过保留 4-甲基哌嗪酰胺官能团（C-3）和 TZ 部分在 N-15 位，并在芳环上引入其他吸电子邻位、间位和/或对位取代基，以改善药物动力学特性并提高杀锥虫活性，从而进行优化。
