Universidade Federal de Pernambuco (UFPE), Departamento de Antibióticos, 50670-901 Recife, PE, Brazil; Instituto Aggeu Magalhães, Fundação Oswaldo Cruz (IAM-FIOCRUZ), 50670-420 Recife, PE, Brazil.
Universidade Federal de Pernambuco (UFPE), Departamento de Antibióticos, 50670-901 Recife, PE, Brazil.
Eur J Pharm Sci. 2019 Oct 1;138:104985. doi: 10.1016/j.ejps.2019.104985. Epub 2019 Jul 5.
The present work aimed to carry out in vitro biological assays of indol-3-yl derivatives thiosemicarbazones (2a-e) and 4-thiazolidinones (3a-d) against juvenile and adult worms of S. mansoni, as well as the in silico determination of pharmacokinetic parameters for the prediction of the oral bioavailability of these derivatives. All compounds were initially screened at a concentration of 200 μM against S. mansoni adult worms and the results evidenced the good activity of compounds 2b, 2d and 3b, which caused 100% mortality after 24, 48 and 72 h, respectively. Subsequent studies with these same compounds revealed that compound 2b was able to reduce the viability of the parasites by 85% and 83% at concentrations of 200 and 100 μM, respectively. In relation to the juvenile worms, all compounds (2b, 2d and 3b) were able to cause mortality, but compound 2b demonstrated better activity causing 100% mortality in 48 h. Additionally, it was possible to observe reduction in the viability of juvenile worms of 85%, 81% and 64% at concentrations of 200, 100 and 50 μM, respectively. Several ultrastructural damages were observed when adult and juvenile S. mansoni worms were exposed to compound 2b (200 μM) that was characterized by extensive destruction by the integument, which may justify the mortality rate of cultured parasites. In the DNA interaction assay, fragmentation of the genetic material of adult worms when treated with compound 2b (200 μM) was evidenced, indicating the apoptosis process as mechanism of parasite death. Regarding pharmacokinetic properties, all derivatives are according to the required parameters, predicting good oral bioavailability for the studied compounds. The results presented in this study reveal the good activity of compound 2b in both adult and juvenile worms of S. mansoni, pointing this compound as promising in the development of further studies on schistosomicidal activity.
本工作旨在对吲哚-3-基取代的缩氨基硫脲（2a-e）和 4-噻唑烷酮（3a-d）衍生物进行抗曼氏血吸虫幼体和成虫的体外生物学测定，以及通过计算预测这些衍生物口服生物利用度的药代动力学参数。所有化合物最初在 200μM 浓度下针对曼氏血吸虫成虫进行筛选，结果表明化合物 2b、2d 和 3b 的活性较好，分别在 24、48 和 72 小时后导致 100%的死亡率。对这些相同化合物的进一步研究表明，化合物 2b 在 200 和 100μM 浓度下能够分别将寄生虫的活力降低 85%和 83%。关于幼体，所有化合物（2b、2d 和 3b）都能够导致死亡，但化合物 2b 表现出更好的活性，在 48 小时内导致 100%的死亡率。此外，在 200、100 和 50μM 浓度下，幼体活力分别降低 85%、81%和 64%。当曼氏血吸虫成虫和幼体暴露于化合物 2b（200μM）时，观察到多种超微结构损伤，其特征是被体壁广泛破坏，这可能解释了培养寄生虫的死亡率。在 DNA 相互作用测定中，当用化合物 2b（200μM）处理时，成虫的遗传物质发生断裂，表明凋亡过程是寄生虫死亡的机制。关于药代动力学性质，所有衍生物都符合所需参数，表明研究化合物具有良好的口服生物利用度。本研究结果表明，化合物 2b 对曼氏血吸虫成虫和幼体均具有良好的活性，表明该化合物在开发抗血吸虫活性的进一步研究中具有潜力。
