title: Novel carbazole aminoalcohols as inhibitors of β-hematin formation: Antiplasmodial and antischistosomal activities.
abstract: 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 β-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 μM, PfDd2 IC50= 0.091 μM) and antischistosomal activities (100% mortality of adult and juvenile schistosomes at 5 and 10 μg/mL, respectively) and exhibited low cytotoxicity (CC50= 7.931 μM), 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.
authors.affiliation: 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.
authors.forename: Weisi
authors.initials: W
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Yufen
authors.initials: Y
authors.lastname: Wei
authors.affiliation: 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.
authors.forename: Jian
authors.initials: J
authors.lastname: Xue
authors.affiliation: Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Sun
authors.affiliation: Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China.
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Chen
authors.affiliation: 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.
authors.forename: Shizhu
authors.initials: S
authors.lastname: Li
authors.affiliation: 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; Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China. Electronic address: duanlp1@chinacdc.cn.
authors.forename: Liping
authors.initials: L
authors.lastname: Duan
mesh_terms: D000605:Amino Alcohols / Q000138:chemical synthesis / Q000494:pharmacology*; D000818:Animals; D000977:Antiparasitic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D002227:Carbazoles / Q000138:chemical synthesis / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D006420:Hemeproteins / Q000037:antagonists & inhibitors*; D020128:Inhibitory Concentration 50; D010963:Plasmodium falciparum / Q000187:drug effects*; D012549:Schistosoma japonicum / Q000187:drug effects*; D016019:Survival Analysis
chemical_list: D000605:Amino Alcohols; D000977:Antiparasitic Agents; D002227:Carbazoles; D006420:Hemeproteins; C020753:hemozoin
keywords: Antiplasmodials; Antischistosomals; Carbazole aminoalcohols; Hematin; Plasmodium falciparum; Schistosoma japonicum