RESUMEN
Phthalimide, 1,3-thiazole, and thiazolidinone cores are considered privileged scaffolds and represent an attractive starting point to design new bioactive compounds for neglected tropical disease (NTD). Schistosomiasis is a NTD, caused by Schistosoma worms which praziquantel (PZQ) is the only drug used to treat humans, but the decrease in the effect after treatment has been reported. Recently, some phthalimide-thiazole derivatives exhibited in vitro antischistosomal activity against adult worms with significant ultrastructural changes and a lower cytotoxic effect on splenocytes. This new biological phthalimido-thiazole profile has motivated us to evaluate a new generation of such molecules in immature and adult worms. Thus, a phthalimido-thiazolidinone derivative, (3c), and three phthalimido-thiazoles (6c, 7a, and 7h) were evaluated concerning their in vitro activity on schistosomulae and adult worms. The results showed that these compounds brought a significant reduction on the mortality, inhibited oviposition, and then induced mortality in immature and adult worms alike. According to scanning electron microscopy, the tegument was the principal target for 7a and 7h and revealed gradual damage to the tegument surface, inducing destruction and decomposition of the tegument in the same areas and exposition of subtegumental tissue and of muscle tissue. Furthermore, they caused less toxicity in splenocytes than PZQ. Compounds 7a and 7h revealed to possess promising activity against larval forms. According to the present study, the privileged structure phthalimido-thiazoles act as a molecular framework that has antischistosomal activity and most form the basis to the next pre-clinical tests. Graphical abstract.
Asunto(s)
Ftalimidas , Schistosoma mansoni/efectos de los fármacos , Esquistosomiasis mansoni/tratamiento farmacológico , Tiazoles , Animales , Antiprotozoarios/farmacología , Antiprotozoarios/uso terapéutico , Técnicas In Vitro , Microscopía Electrónica de Rastreo , Ftalimidas/química , Ftalimidas/farmacología , Ftalimidas/uso terapéutico , Schistosoma mansoni/ultraestructura , Tiazoles/química , Tiazoles/farmacología , Tiazoles/uso terapéuticoRESUMEN
Schistosomiasis is a major public health problem worldwide, especially in poor communities. Praziquantel is currently the only drug available to treat schistosomiasis and it shows low efficacy against schistosomula and juveniles stages of Schistosoma mansoni, allowing lower cure rate in areas with high endemicity. There is an urgent need to identify new antischistosomal drugs. Previous works identified phthalimido-thiazoles as privileged structures acting as schistossomicidal agent. In this way, a phthalimido-thiosemicarbazide intermediate and eight phthalimido-thiazoles derivatives were evaluated concerning the in vitro antischistosomal activity compounds in adult phase of Schistosoma mansoni and examined alterations on the tegumental surface. The results revealed that compounds 2f, 2â¯l and 2â¯m caused significant mortality in adult worms at concentrations range of 20⯵g/mL to 100⯵g/mL. These compounds were also selected in view to verify the activity against the schistosomula. Compound 2â¯m promoted 100% of mortality of larval forms until doses of 2.5⯵g/mL within 48â¯h. In addition, when compound 2â¯m was administered orally at dose of 200â¯mg/kg for 5 consecutive days to the infected mouse with adult schistosomes, a reduction in the parasite burden was observed. Furthermore, scanning electron microscopy revealed that compound 2â¯m kill the parasite by tegumental damage and bubbles generation.