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

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 M and significant molluscicidal activity, with a 50% lethal concentration (LC 50 ) 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. S chistosomiasis japonica, caused by infection withSchistosoma japonicum, is recognized as a considerable economic and public health concern in Asia, including China, Indonesia, and the Philippines (1-3). According to estimates, over 58 million people are infected (4). Schistosome infection occurs through contact with water contaminated by cercariae, the free-living stage of the parasite shed from intermediate host Oncomelania snails (5). Although praziquantel is available for treatment, there is the fact that it cannot prevent individuals from reinfection. Repeated and intense exposure to cercariae could lead to an ineffective response of early-stage chronic cases in routine control programs, which would increase the risk of infections progressing to an advanced stage. A successful control program of the disease should be constructed as an integrated control scheme including cercaricidal methods, snail control programs, and chemotherapy.Niclosamide has a long track record as a successful molluscicide against Oncomelania snails (6, 7). Moreover, it is effective for cercaria control both under laboratory conditions and in field experiments (8-10). However, niclosamide has relatively poor solubility in water and is a well-known environmentally hazardous chemical. It has been proved highly toxic to 18 species of fish (11). It exhibited strong to moderate cytotoxicity on several human cell lines (12, 13). In the last 2 decades, most of the modifications of niclosamide have focused on improving its so...

Molluscicidal activity and mechanism of toxicity of a novel salicylanilide ester derivative against Biomphalaria species

“…Niclosamide was used as positive control, and dechlorinated water mixed with DMSO (no compounds) was used as a negative control. Snails were considered dead according to one or more of the following criteria: discoloration, contraction of the hemolymph [ 21 ], absence of muscle contraction and heart activity [ 22 ], hemorrhage and deterioration of the body tissues [ 19 ]. The 50%/90% lethal concentration (LC 50 /LC 90 ) values, as well as their 95% confidence limits, were determined through probit analysis.…”

“…Our previous studies demonstrated that a salicylanilide ester derivative exhibited similar activity against Oncomelania hupensis and negligible toxicity to human kidney cells and Danio rerio compared with that of niclosamide [ 19 ]. Based on these findings, salicylanilidate was optimized as a novel compound from niclosamide by 4-methoxyphenyl ester substituent at the hydroxyl group and then evaluated for cercaricidal potential against S. mansoni and molluscicidal potential against crucial intermediate hosts of S. mansoni in the present study.…”

A New Method to Test Molluscicides against the Philippine Schistosomiasis Snail Vectors

“…e broad toxicity of niclosamide to many nontarget organisms such as fish and amphibians is the major concern against its use in mass application [5]. us, there are new attempts to develop novel molluscicides by optimizing the activity of known substances or tapping diverse compounds from natural sources [7][8][9][10].…”

“…ere is a growing interest in phytochemicals with potent molluscicidal activity a er the successful use of Phytolacca dodecandra in the snail population control of schistosome vectors in Egypt [7,8,11]. Synthesis of new compounds and structure-activity relationship with known molluscicides are also gaining popularity [9,10,12,13]. Both research strategies will require an assay which uses a small amount of test substance while maintaining accuracy and reproducibility.…”

Deficiência De Vitamina D Em Pacientes Submetidos À Cirurgia Bariátrica

“…Pela ausência de vacina, as ações que se têm realizado para combater a parasitose são inquéritos malacológicos, o diagnóstico e o tratamento dos esquistossomóticos com o fármaco praziquantel(PEREIRA et al, 2017). Estas atividades têm diminuído o índice de formas clínicas graves, porém não têm reduzido a prevalência e nem impedido a transmissão da endemia, de forma que o doente pode adquiri-la novamente(CANTANHEDE et al, 2010).Em função destas circunstâncias, muitos pesquisadores sugerem como estratégia promissora para o controle da helmintíase em médio e longo prazo o controle dos moluscos hospedeiros conjugado com a quimioterapia, as obras sanitárias e as práticas de educação em saúdeCALDEIRA, 2016;WANG et al, 2016;.O controle dos caramujos transmissores pode ser realizado, dentre outros métodos, por meio da aplicação de moluscicidas nos seus criadouros naturais. O moluscicida sintético niclosamida, comercialmente conhecido como Bayluscide®, possui alta eficiência contra todos os estágios de desenvolvimento dos caramujos Biomphalaria e formas larvárias de Schistosoma(BRASIL, 2008;MATA et al, 2011;MARTINS et al, 2017).…”