National Institute of Parasitic Diseases, Chinese Center for Disease Control and Prevention (Chinese Center for Tropical Diseases Research), National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, NHC Key Laboratory of Parasite and Vector Biology, WHO Collaborating Centre for Tropical Diseases, National Center for International Research on Tropical Diseases, Shanghai 200025, China.
J Antimicrob Chemother. 2024 Jul 1;79(7):1606-1613. doi: 10.1093/jac/dkae149.
The efficacy of current drugs against hookworms at a single dose is highly variable across regions, age groups and infection intensity. Extensive and repeated use of these drugs also leads to potential drug resistance. Therefore, novel drugs are required for sustained disease control.
Novel aromatic heterocycle substituted aminamidine derivatives (AADs) were synthesized based on tribendimine (TBD), and their in vivo potency against Necator americanus was tested.
The efficacy of the AADs was tested in male hamsters. Oral and IV pharmacokinetic parameters were determined in male Sprague-Dawley rats. The proteomic profiles of N. americanus samples treated with AADs were compared using tandem mass tag-based quantitative proteomic analyses.
Most AADs exhibited better anthelmintic activity than TBD at a single oral dose. Compound 3c exhibited improved solubility (>50×), and the curative dose was as low as 25 mg/kg. Similar to TBD, 3c was rapidly metabolized after oral administration and transformed into p-(1-dimethylamino ethylimino)aniline (dADT), an active metabolite against intestinal nematodes. dADT from 3c had better pharmacokinetic profiles than that from TBD and achieved an oral bioavailability of 99.5%. Compound 3c possessed rapid anthelmintic activity, clearing all worms within 24 h after an oral dose of 50 mg/kg. Quantitative proteomic analysis indicated that it might be related to ATP metabolism and cuticle protein synthesis.
Compound 3c is a novel and promising compound against N. americanus in vivo.
目前针对钩虫的单一剂量药物在不同地区、年龄组和感染强度下的疗效差异很大。这些药物的广泛和重复使用也会导致潜在的药物耐药性。因此，需要新型药物来持续控制疾病。
基于三苯并咪嗪（TBD）合成了新型芳杂环取代的脒基脒衍生物（AAD），并测试了其对美洲钩虫的体内疗效。
在雄性仓鼠中测试 AAD 的疗效。在雄性 Sprague-Dawley 大鼠中测定口服和 IV 药代动力学参数。使用串联质量标签定量蛋白质组学分析比较 AAD 处理的美洲钩虫样本的蛋白质组学图谱。
大多数 AAD 在单次口服剂量下的驱虫活性均优于 TBD。化合物 3c 表现出更好的溶解性（>50×），治疗剂量低至 25mg/kg。与 TBD 相似，3c 经口服给药后迅速代谢，并转化为对肠道线虫具有活性的代谢物 p-(1-二甲基氨基乙基亚氨基)苯胺（dADT）。来自 3c 的 dADT 具有比来自 TBD 的更好的药代动力学特征，口服生物利用度达到 99.5%。化合物 3c 具有快速的驱虫活性，在口服 50mg/kg 后 24 小时内可清除所有蠕虫。定量蛋白质组学分析表明，它可能与 ATP 代谢和角质层蛋白合成有关。
化合物 3c 是一种新型的、有前途的体内抗美洲钩虫化合物。
