Dados do Trabalho

Título

New thiazolidine derivatives candidates for schistosomicidal drugs: in vitro evaluation against young worms and adult couples of Schistosoma mansoni

Objetivo (s)

We aimed to evaluate the in vitro schistosomicidal action of new thiazolidines (TZDs) against young worms and adult couples of S. mansoni, its cytotoxicity, and tegumentary alterations in the worms.

Material e Métodos

The Synthesis was followed by nucleophilic reaction, reaction with 4-hydroxy-benzaldehyde, and cyclization with phenyl-, 4-bromophenyl-, 4-chlorophenyl-, 4-nitrophenyl, to obtain compounds LQIT-PBT1, LQIT-PBT2, and LQIT-PBT3. Mice were infected with S. mansoni and the hepatic portal system/mesenteric vessels were perfused to obtain young worms and adult couples on the 21st or 45th day of infection, respectively. Worms were distributed in culture plates (30 juveniles or 2 adult couples/well in sextuplicate) and incubated in 6.25-200 μM of compounds for motor assessment and mortality at intervals of 3, 6, 12, and 24h and then for five consecutive days. Worms incubated in Praziquantel (PZQ) (10 μM) or RPMI medium alone formed positive and negative controls, respectively.

Resultados e Conclusão

The negative control showed typical motility, topography, and peristalsis and PZQ caused 100% mortality after 24h with morphological changes and tegumentary damage. For young worms, LQIT-PBT-01 caused total mortalityafter 120h at 200, 100 and 50 μM and 83.4% at 25 μM. In this range, LQIT-PBT-03 caused 100, 47, and 36% mortality at 200, 100, and 50 µM. Already 200 and 100 μM of LQIT-PBT-02 caused 100% mortality after 24 and 48h, respectively. For adult couples, LQIT-PBT-01 caused 100% mortality at 200 µM after 120h, whereas LQIT-PBT-03 resulted in 12.5% mortality at 200 µM. On the other hand, after 3h, LQIT-PBT-02 caused 100 and 87% mortality at 200 and 100 μM, respectively, and after 120h mortality of 50% at 50 μM. Other concentrations caused changes in motility, reduced peristalsis, and unmating. In addition, tegumentary alterations were evidenced by scanning electron microscopy, such as blisters, desquamation, exposure of subcutaneous tissue, and shortening of the worms. All compounds caused a dose-dependent reduction in cell viability of young worms and couples, with emphasis on LQIT-PBT-02, which was more effective than PZQ. Cellular cytotoxicity demonstrated that the compounds are less toxic than PZQ. Thus, the unprecedented compound LQIT-PBT-02, after new in vivo evaluations and pharmacokinetic and dynamic studies, may represent a new alternative for treating and controlling schistosomiasis.

Palavras-chave

Schistosomicidal activity, medicinal chemistry

Agradecimentos

CAPES, FACEPE