Ebiloma Godwin U, Ayuga Teresa Díaz, Balogun Emmanuel O, Gil Lucía Abad, Donachie Anne, Kaiser Marcel, Herraiz Tomás, Inaoka Daniel K, Shiba Tomoo, Harada Shigeharu, Kita Kiyoshi, de Koning Harry P, Dardonville Christophe
Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom; Department of Biochemistry, Kogi State University, Anyigba, Nigeria.
Instituto de Química Médica, IQM-CSIC, Juan de la Cierva 3, E-28006 Madrid, Spain.
Eur J Med Chem. 2018 Apr 25;150:385-402. doi: 10.1016/j.ejmech.2018.02.075. Epub 2018 Feb 26.
African trypanosomiasis is a neglected parasitic disease that is still of great public health relevance, and a severe impediment to agriculture in endemic areas. The pathogens possess certain unique metabolic features that can be exploited for the development of new drugs. Notably, they rely on an essential, mitochondrially-localized enzyme, Trypanosome Alternative Oxidase (TAO) for their energy metabolism, which is absent in the mammalian hosts and therefore an attractive target for the design of safe drugs. In this study, we cloned, expressed and purified the physiologically relevant form of TAO, which lacks the N-terminal 25 amino acid mitochondrial targeting sequence (ΔMTS-TAO). A new class of 32 cationic and non-cationic 4-hydroxybenzoate and 4-alkoxybenzaldehyde inhibitors was designed and synthesized, enabling the first structure-activity relationship studies on ΔMTS-TAO. Remarkably, we obtained compounds with enzyme inhibition values (IC) as low as 2 nM, which were efficacious against wild type and multidrug-resistant strains of T. brucei and T. congolense. The inhibitors 13, 15, 16, 19, and 30, designed with a mitochondrion-targeting lipophilic cation tail, displayed trypanocidal potencies comparable to the reference drugs pentamidine and diminazene, and showed no cross-resistance with the critical diamidine and melaminophenyl arsenical classes of trypanocides. The cationic inhibitors 15, 16, 19, 20, and 30 were also much more selective (900 - 344,000) over human cells than the non-targeted neutral derivatives (selectivity >8-fold). A preliminary in vivo study showed that modest doses of 15 and 16 reduced parasitaemia of mice infected with T. b. rhodesiense (STIB900). These compounds represent a promising new class of potent and selective hits against African trypanosomes.
非洲锥虫病是一种被忽视的寄生虫病，至今仍具有重大的公共卫生意义，并且是流行地区农业发展的严重障碍。这些病原体具有某些独特的代谢特征，可用于开发新药。值得注意的是，它们的能量代谢依赖于一种必需的、定位于线粒体的酶——锥虫替代氧化酶（TAO），而哺乳动物宿主中不存在这种酶，因此它是设计安全药物的一个有吸引力的靶点。在本研究中，我们克隆、表达并纯化了缺乏N端25个氨基酸线粒体靶向序列的生理相关形式的TAO（ΔMTS-TAO）。设计并合成了一类新的32种阳离子和非阳离子4-羟基苯甲酸酯和4-烷氧基苯甲醛抑制剂，从而能够首次对ΔMTS-TAO进行构效关系研究。值得注意的是，我们获得了酶抑制值（IC）低至2 nM的化合物，这些化合物对布氏锥虫和刚果锥虫的野生型和多药耐药菌株均有效。设计有靶向线粒体的亲脂性阳离子尾部的抑制剂13、15、16、19和30，显示出与参考药物喷他脒和二脒那秦相当的杀锥虫效力，并且与关键的二脒类和氨基苯基胂类杀锥虫剂没有交叉耐药性。阳离子抑制剂15、16、19、20和30对人细胞的选择性（900 - 344,000）也比非靶向中性衍生物高得多（选择性>8倍）。一项初步的体内研究表明，适量剂量的15和16可降低感染罗德西亚布氏锥虫（STIB900）的小鼠的寄生虫血症。这些化合物代表了一类有前景的新型强效且选择性的抗非洲锥虫药物。
