Synthesis, Bioactivity Evaluation, and Toxicity Assessment of Novel Salicylanilide Ester Derivatives as Cercaricides against Schistosoma japonicum and Molluscicides against Oncomelania hupensis

Antimicrob Agents Chemother. 2015 Oct 26;60(1):323-31. doi: 10.1128/AAC.01539-15. Print 2016 Jan.


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.

MeSH terms

  • Acetylcholinesterase / metabolism
  • Animals
  • Anthelmintics / chemical synthesis
  • Anthelmintics / pharmacology*
  • Dose-Response Relationship, Drug
  • Esters
  • Female
  • Gastropoda / drug effects*
  • Gastropoda / physiology
  • HEK293 Cells
  • Humans
  • Inhibitory Concentration 50
  • L-Lactate Dehydrogenase / metabolism
  • Male
  • Molluscacides / chemical synthesis
  • Molluscacides / pharmacology*
  • Niclosamide / pharmacology
  • Nitric Oxide Synthase / antagonists & inhibitors
  • Nitric Oxide Synthase / metabolism
  • Parasitic Sensitivity Tests
  • Salicylanilides / chemical synthesis
  • Salicylanilides / pharmacology*
  • Schistosoma japonicum / drug effects*
  • Schistosoma japonicum / physiology
  • Structure-Activity Relationship
  • Zebrafish


  • Anthelmintics
  • Esters
  • Molluscacides
  • Salicylanilides
  • Niclosamide
  • L-Lactate Dehydrogenase
  • Nitric Oxide Synthase
  • Acetylcholinesterase