National Institute of Parasitic Diseases, Chinese Center for Disease Control and Prevention, WHO Collaborating Centre for Malaria, Schistosomiasis, and Filariasis, Key Laboratory of Parasitology and Vector Biology of the Chinese Ministry of Health, Shanghai 200025, China.
ZJU-ENS Joint Laboratory of Medicinal Chemistry, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
J Antimicrob Chemother. 2017 Nov 1;72(11):3122-3130. doi: 10.1093/jac/dkx250.
Cystic echinococcosis (CE), caused by the cestode Echinococcus granulosus, is a worldwide chronic zoonosis. Current chemotherapeutic options are limited to albendazole and mebendazole, which only exert parasitostatic effects and have to be administered at high dosages for long periods. In an effort to find alternative treatment options, the in vitro and in vivo efficacies of novel carbazole aminoalcohols were evaluated.
Carbazole aminoalcohols were tested against E. granulosus protoscoleces in vitro and metacestodes ex vivo. The in vivo chemotherapeutic effect of representative compounds was assessed in experimentally infected mice. Oral and intravenous pharmacokinetic profiles were determined in mice.
The carbazole aminoalcohols exhibited potent protoscolicidal activity with LC50 values ranging from 18.2 to 34.3 μM. Among them, compounds 2 and 24 killed all ex vivo cultured metacestodes at concentrations of 34.3 and 30.6 μM. In vivo studies showed that oral administration of compounds 2 and 24 (25 mg/kg/day) for 30 days led to reductions of 68.4% and 54.3% in parasite weight compared with the untreated group (both groups: P < 0.001). Compound 2 (25 mg/kg/day) and compound 24 (50 mg/kg/day) induced significantly higher cyst mortality rates in comparison with that of the albendazole group (both groups: P < 0.01). Analysis of cysts collected from compound 2- or 24-treated mice by transmission electron microscopy revealed a drug-induced structural destruction. The structural integrity of the germinal layer was lost, and the majority of the microtriches disappeared. Pharmacokinetic profiling of compounds 2 and 24 revealed low clearance and decent oral bioavailability (>70%).
Our study identifies carbazole aminoalcohols as a class of novel anti-CE agents. Compounds 2 and 24 represent promising drug candidates in anti-CE chemotherapy.
由绦虫棘球蚴引起的包虫病（CE）是一种全球性的慢性人畜共患病。目前的化学治疗选择仅限于阿苯达唑和甲苯达唑，它们仅发挥寄生虫静止作用，必须高剂量长时间使用。为了寻找替代治疗方法，评估了新型咔唑氨基醇的体外和体内疗效。
在体外和体内检测咔唑氨基醇对棘球蚴原头节和体外包虫的作用。在实验感染的小鼠中评估代表性化合物的体内化学治疗效果。在小鼠中确定口服和静脉内药代动力学特征。
咔唑氨基醇表现出强大的原头节杀幼虫活性，LC50 值范围为 18.2 至 34.3 μM。其中，化合物 2 和 24 在浓度为 34.3 和 30.6 μM 时可杀死所有体外培养的包虫。体内研究表明，口服给予化合物 2 和 24（25mg/kg/天）30 天可使寄生虫重量分别减少 68.4%和 54.3%，与未治疗组相比（两组：P<0.001）。与阿苯达唑组相比，化合物 2（25mg/kg/天）和化合物 24（50mg/kg/天）诱导的囊肿死亡率显著更高（两组：P<0.01）。透射电子显微镜分析来自化合物 2 或 24 处理的小鼠收集的囊肿显示药物诱导的结构破坏。生发层的结构完整性丧失，并且大多数微毛消失。化合物 2 和 24 的药代动力学特征显示出低清除率和良好的口服生物利用度（>70%）。
本研究确定咔唑氨基醇为一类新型抗 CE 药物。化合物 2 和 24 是抗 CE 化学疗法的有前途的候选药物。
