Phthalimido-thiazole as privileged scaffold: activity against immature and adult worms of Schistosoma mansoni.

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.

New 1,3-thiazole derivatives and their biological and ultrastructural effects on Trypanosoma cruzi.

In previous studies, the compound 3-(bromopropiophenone) thiosemicarbazone was described as a potent anti-Trypanosoma cruzi and cruzain inhibitor. In view to optimize this activity, 1,3-thiazole core was used as building-block strategy to access new lead generation of anti T. cruzi agents. In this way a series of thiazole derivatives were synthesized and most of these derivatives exhibited antiparasitic activity similar to benznidazole (Bzd). Among them, compounds (1c) and (1g) presented better selective index (SI) than Bzd. In addition, compounds showed inhibitory activity against the cruzain protease. As observed by electron microscopy, compound (1c) treatment caused irreversible and specific morphological changes on ultrastructure organization of T. cruzi, demonstrating that this class of compounds is killing parasites.

In vivo study of schistosomicidal action of 1-benzyl-4-[(4-fluoro-phenyl)-hydrazono]-5-thioxo-imidazolidin-2-one.

Praziquantel has been the drug most widely used therapy against different forms of schistosomiasis around the world. However, this treatment has shown ineffective in humans and in experimental models of Schistosoma mansoni. New therapeutic alternatives have been tested, including the imidazolidine derivative LPSF/PT-09, which has shown high therapeutic potential in vitro. In this work, we tested the schistosomal activity of this derivative in doses of 250mg/kg and 200mg/kg in mice experimentally infected with a high parasite load of S. mansoni. Parasitological evaluations related to the number of S. mansoni worms and their oviposition were performed during the acute phase of the disease and have demonstrated moderate effectiveness of 30-54,4%. However, LPSF/PT-09 did not influence oviposition of the parasites or the embryonic development of the eggs. The results obtained in this model showed that the imidazolidine derivative LPSF/PT-09 presented significant antischistosomal activity in vivo, posing as a potential candidate for this class of drugs. However, a better understanding of the pharmacokinetics and pharmacodynamics of the imidazolidine derivative LPSF/PT-09 is needed.