Novel 3-Nitro-1H-1,2,4-triazole-Based Aliphatic and Aromatic Amines as Anti-Chagasic Agents

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• 作者：Maria V. Papadopoulou ; Bernadette Bourdin Trunz ; William D. Bloomer ; Caroline McKenzie ; Shane R. Wilkinson ; Chaiya Prasittichai ; Reto Brun ; Marcel Kaiser ; Els Torreele
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：December 8, 2011
• 年：2011
• 卷：54
• 期：23
• 页码：8214-8223
• 全文大小：464K
• 年卷期：v.54,no.23(December 8, 2011)
• ISSN：1520-4804

文摘

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 (IC₅₀ ranging from 40 nM to 1.97 渭M), without concomitant toxicity toward the host cells (L6 cells), having selectivity indices (SI) 44鈥?320. 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 (IC₅₀ at nM levels and SI 220鈥?93). 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.