Discovery of an orally active nitrothiophene-based antitrypanosomal agent.
Discovery of an orally active nitrothiophene-based antitrypanosomal agent.
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发现一种口服活性硝基噻吩类抗锥虫药。
DOI：
10.1016/j.ejmech.2023.115954
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发表时间：
2024
影响因子：
6.7
通讯作者：
Ogungbe,IfedayoVictor
中科院分区：
文献类型：
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作者：
Ajayi,Oluwatomi;Metibemu,DamilohunS;Crown,Olamide;Adeyinka,OlawaleS;Kaiser,Marcel;Shoji,Nathalie;Silva,Mariana;Rodriguez,Ana;Ogungbe,IfedayoVictor
非洲人类锥虫病（HAT）是由布氏冈比亚锥虫和罗得西亚锥虫引起的，是撒哈拉以南非洲地区流行的一种寄生虫病。未经治疗的 HAT 病例可能会导致严重衰弱甚至致命。尽管报告的病例数量在过去十年中逐渐减少，但有效且易于服用的药物数量非常有限。在这项工作中，我们报告了一系列有效化合物的抗锥虫活性。该系列中的一部分分子对锥虫具有高度选择性，并且代谢稳定。其中一种化合物 (E)-N-(4-(甲基氨基)-4-oxobut-2-en-1-yl)-5-硝基噻吩-2-甲酰胺 (10) 选择性抑制 T 的生长。 b.布鲁塞，T. b.冈比亚和 T. b. rhodesense 具有优异的口服生物利用度，可有效治疗小鼠模型的 HAT 急性感染。基于其优异的生物利用度，compound10 及其类似物是先导化合物优化和临床前研究的候选药物。
Human African Trypanosomiasis (HAT), caused byTrypanosoma brucei gambiense and rhodesiense,is a parasitic disease endemic to sub-Saharan Africa. Untreated cases of HAT can be severely debilitating and fatal. Although the number of reported cases has decreased progressively over the last decade, the number of effective and easily administered medications is very limited. In this work, we report the antitrypanosomal activity of a series of potent compounds. A subset of molecules in the series are highly selective for trypanosomes and are metabolically stable. One of the compounds, (E)-N-(4-(methylamino)-4-oxobut-2-en-1-yl)-5-nitrothiophene-2-carboxamide (10), selectively inhibited the growth ofT. b. brucei, T. b. gambiense and T. b. rhodesiense,have excellent oral bioavailability and was effective in treating acute infection of HAT in mouse models. Based on its excellent bioavailability, compound10and its analogs are candidates for lead optimization and pre-clinical investigations.