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

Abstract

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.

Assessment of tegumental damage to Schistosoma mansoni and S. haematobium after in vitro exposure to ferrocenyl, ruthenocenyl and benzyl derivatives of oxamniquine using scanning electron microscopy

“…Artemether for example, causes extensive peeling in females but not in males [ 16 ]. Overall, the tegumental changes observed resemble findings from previous studies with praziquantel and other lead candidates, which also mention loss of spines, blebs and sloughing tissue with exposure of sub-tegumental tissue [ 17 , 18 ].…”

Endometriose: repercussões clínicas e seu impacto na fertilidade feminina

“…A endometriose pode causar infertilidade por meio de vários mecanismos, como alterações imunológicas; influencia hormonal na ovulação e na implantação do embrião; alteração do hormônio prolactina e as prostaglandinas que agem negativamente na fertilidade; anormalidades anatômicas dos ovários, tubas uterinas e útero, devido adesões e formação de endometriomas; prejuízos na função ovariana, como redução na qualidade dos oócitos e liberação do óvulo; dificuldade no transporte do óvulo pela tuba uterina, devido a aderências; receptividade endometrial, a endometriose produz substâncias que atrapalham a implantação do embrião 9 .…”

Phthalimide as a versatile pharmacophore scaffold: Unlocking its diverse biological activities

“…Compounds 332–334 , 336–340 , and 342 reported inhibition values in the range of 25%–75% (Singh et al, 2020). In another study, De Oliveira et al (2018) evaluated the anti‐ S. mansoni effects of phthalimides 343–346 (Figure 27) over a longer period of 192 h. Compounds ( 344–346 ) showed 100% inhibition against adult forms of S. mansoni , while compound 343 exhibited inhibition of 54%. Moreover, the four compounds were evaluated for their cytotoxicity effects in the spleen cells of Balb/c mice, with CC 50 values in the range of 138.09–302.97 µM (De Oliveira et al, 2018).…”