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Synthesis, Bioactivity Evaluation, and Toxicity Assessment of Novel Salicylanilide Ester Derivatives as Cercaricides against Schistosoma japonicum and Molluscicides against Oncomelania hupensis.
- Source :
-
Antimicrobial agents and chemotherapy [Antimicrob Agents Chemother] 2015 Oct 26; Vol. 60 (1), pp. 323-31. Date of Electronic Publication: 2015 Oct 26 (Print Publication: 2016). - Publication Year :
- 2015
-
Abstract
- 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.<br /> (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)
- Subjects :
- Acetylcholinesterase metabolism
Animals
Anthelmintics chemical synthesis
Dose-Response Relationship, Drug
Esters
Female
Gastropoda physiology
HEK293 Cells
Humans
Inhibitory Concentration 50
L-Lactate Dehydrogenase metabolism
Male
Molluscacides chemical synthesis
Niclosamide pharmacology
Nitric Oxide Synthase antagonists & inhibitors
Nitric Oxide Synthase metabolism
Parasitic Sensitivity Tests
Salicylanilides chemical synthesis
Schistosoma japonicum physiology
Structure-Activity Relationship
Zebrafish
Anthelmintics pharmacology
Gastropoda drug effects
Molluscacides pharmacology
Salicylanilides pharmacology
Schistosoma japonicum drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1098-6596
- Volume :
- 60
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Antimicrobial agents and chemotherapy
- Publication Type :
- Academic Journal
- Accession number :
- 26503661
- Full Text :
- https://doi.org/10.1128/AAC.01539-15