文献类型：期刊文献

英文题名：Novel carbazole aminoalcohols as inhibitors of β-hematin formation: Antiplasmodial and antischistosomal activities

作者：Wang, Weisi[1,2];Li, Qiang[1];Wei, Yufen[1];Xue, Jian[1];Sun, Xiao[3];Yu, Yang[3];Chen, Zhuo[3];Li, Shizhu[1];Duan, Liping[1,4]

机构：[1]Chinese Minist Hlth, Key Lab Parasitol & Vector Biol, Natl Inst Parasit Dis,Chinese Ctr Dis Control & P, WHO Collaborating Ctr Malaria Schistosomiasis & F, Shanghai 200025, Peoples R China;[2]Zhejiang Univ, Coll Pharmaceut Sci, ZJU ENS Joint Lab Med Chem, Hangzhou 310058, Zhejiang, Peoples R China;[3]East China Univ Sci & Technol, Shanghai Key Lab New Drug Design, Sch Pharm, Shanghai 200237, Peoples R China;[4]Chinese Acad Sci, Inst Microbiol, Beijing 100101, Peoples R China

年份：2017

卷号：7

期号：2

起止页码：191

外文期刊名：INTERNATIONAL JOURNAL FOR PARASITOLOGY-DRUGS AND DRUG RESISTANCE

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000407702600007)】；

基金：This work was supported by China Postdoctoral Science Foundation funded project (grant number 2015M571147), the National Natural Science Foundation of China (grant numbers 21502181 and 21302054), Shanghai Municipal Commission of Health and Family Planning funded project (grant number 201440537) and the project of echinococcosis prevention and control - Ganzi workstation.

语种：英文

外文关键词：Carbazole aminoalcohols; Plasmodium falciparum; Schistosoma japonicum; Antiplasmodials; Antischistosomals; Hematin

摘要：Malaria and schistosomiasis are two of the most socioeconomically devastating parasitic diseases in tropical and subtropical countries. Since current chemotherapeutic options are limited and defective, there is an urgent need to develop novel antiplasmodials and antischistosomals. Hemozoin is a disposal product formed from the hemoglobin digestion by some blood-feeding parasites. Hemozoin formation is an essential process for the parasites to detoxify free heme, which is a reliable therapeutic target for identifying novel antiparasitic agents. A series of novel carbazole aminoalcohols were designed and synthesized as potential antiplasmodial and antischistosomal agents, and several compounds showed potent in vitro activities against Plasmodium falciparum 3D7 and Dd2 strains and adult and juvenile Schistosoma japonicum. Investigations on the dual antiparasitic mechanisms showed the correlation between inhibitory activity of beta-hematin formation and antiparasitic activity. Inhibiting hemozoin formation was identified as one of the mechanisms of action of carbazole aminoalcohols. Compound 7 displayed potent antiplasmodial (Pf3D7 IC50 = 0.248 mu M, PfDd2 IC50 = 0.091 mu M) and antischistosomal activities (100% mortality of adult and juvenile schistosomes at 5 and 10 mu g/mL, respectively) and exhibited low cytotoxicity (CC50 = 7.931 mu M), which could be considered as a promising lead for further investigation. Stoichiometry determination and molecular docking studies were also performed to explain the mode of action of compound 7. (C) 2017 The Authors. Published by Elsevier Ltd on behalf of Australian Society for Parasitology.