NorthShore University HealthSystem, Department of Radiation Medicine, Evanston, Illinois 60201, United States.
J Med Chem. 2011 Dec 8;54(23):8214-23. doi: 10.1021/jm201215n. Epub 2011 Nov 4.
A series of novel 2-nitro-1H-imidazole- and 3-nitro-1H-1,2,4-triazole-based aromatic and aliphatic amines were screened for antitrypanosomal activity and mammalian cytotoxicity by the Drugs for Neglected Diseases initiative (DNDi). Out of 42 compounds tested, 18 3-nitro-1,2,4-triazoles and one 2-nitroimidazole displayed significant growth inhibitory properties against T. cruzi amastigotes (IC(50) ranging from 40 nM to 1.97 μM), without concomitant toxicity toward the host cells (L6 cells), having selectivity indices (SI) 44-1320. Most (16) of these active compounds were up to 33.8-fold more potent than the reference drug benznidazole, tested in parallel. Five novel 3-nitro-1,2,4-triazoles were active against bloodstream-form (BSF) T. b. rhodesiense trypomastigotes (IC(50) at nM levels and SI 220-993). An NADH-dependent nitroreductase (TbNTR) plays a role in the antiparasitic activity because BSF T. b. brucei trypomastigotes with elevated TbNTR levels were hypersensitive to tested compounds. Therefore, a novel class of affordable 3-nitro-1,2,4-triazole-based compounds with antitrypanosomal activity has been identified.
受疾病药物研发倡议组织（DNDi）委托，研究人员对一系列新型 2-硝基-1H-咪唑和 3-硝基-1H-1,2,4-三唑芳基和脂肪族胺进行了抗锥虫活性和哺乳动物细胞毒性筛选。在测试的 42 种化合物中，有 18 种 3-硝基-1,2,4-三唑和 1 种 2-硝基咪唑对 T. cruzi 无鞭毛体具有显著的生长抑制特性（IC50 范围为 40 nM 至 1.97 μM），同时对宿主细胞（L6 细胞）没有毒性，其选择性指数（SI）为 44-1320。这些活性化合物中大多数（16 种）比平行测试的参考药物苯并硝唑的活性高 33.8 倍。5 种新型 3-硝基-1,2,4-三唑对血流形式（BSF）T. b. rhodesiense 锥虫具有活性（IC50 在纳摩尔水平，SI 为 220-993）。NADH 依赖性硝基还原酶（TbNTR）在抗寄生虫活性中发挥作用，因为 TbNTR 水平升高的 BSF T. b. brucei 锥虫对测试化合物高度敏感。因此，已确定了一类具有抗锥虫活性的新型、负担得起的 3-硝基-1,2,4-三唑类化合物。
