Synthesis, Bioactivity Evaluation, and Toxicity Assessment of Novel Salicylanilide Ester Derivatives as Cercaricides against Schistosoma japonicum and Molluscicides against Oncomelania hupensis.
A series of novel salicylanilide ester derivatives were synthesized, characterized, and evaluated for cercaricidal potential against Schistosoma japonicum and molluscicidal potential against Oncomelania hupensis. Four derivatives exhibited remarkable cercaricidal activity superior to that of niclosamide. Among them, the most active compound, 4-chloro-2-((2-methoxy-4-nitrophenyl)carbamoyl)phenyl 4-methoxybenzoate (compound 4c), showed a marked minimum effective cercaricidal concentration as low as 0.43 μM and significant molluscicidal activity, with a 50% lethal concentration (LC50) of 0.206 g/m(2). Particularly, compound 4c displayed 88-fold decreased fish toxicity on Danio rerio and 44-fold reduced cytotoxicity on human kidney HEK293 cells in comparison with the toxicity of niclosamide. The results indicated that 4c could serve as a promising drug candidate, with environmental safety properties, against Schistosoma japonicum at transmission stages. The preliminary molecular mechanism of target compounds in Schistosoma japonicum cercariae was also investigated. Salicylanilide ester derivatives exhibited an inhibitory effect on nitric oxide synthase (NOS) but no effect on lactate dehydrogenase (LDH) and acetylcholinesterase (AChE), and a strong and significant correlation between NOS inhibitory efficacy and cercaricidal activity was observed. In addition, 4c could downregulate the expression of NOS in a dose-dependent manner. These results suggested that NOS was probably one of the drug targets of salicylanilide esters.
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, China.
Weisi
W
Wang
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, China.
Zhiqiang
Z
Qin
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, China.
Dan
D
Zhu
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, China.
Yufen
Y
Wei
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, China.
Shizhu
S
Li
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, China Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China duanlp1@chinacdc.cn.
Liping
L
Duan
D000110:Acetylcholinesterase / Q000378:metabolism; D000818:Animals; D000871:Anthelmintics / Q000138:chemical synthesis / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004952:Esters; D005260:Female; D049851:Gastropoda / Q000187:drug effects* / Q000502:physiology; D057809:HEK293 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D008975:Molluscacides / Q000138:chemical synthesis / Q000494:pharmacology*; D009534:Niclosamide / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D021261:Parasitic Sensitivity Tests; D012458:Salicylanilides / Q000138:chemical synthesis / Q000494:pharmacology*; D012549:Schistosoma japonicum / Q000187:drug effects* / Q000502:physiology; D013329:Structure-Activity Relationship; D015027:Zebrafish
D000871:Anthelmintics; D004952:Esters; D008975:Molluscacides; D012458:Salicylanilides; D009534:Niclosamide; D007770:L-Lactate Dehydrogenase; D019001:Nitric Oxide Synthase; D000110:Acetylcholinesterase