Therapeutic potential of hydantoin and thiohydantoin compounds against Schistosoma mansoni: An integrated in vitro, DNA, ultrastructural, and ADMET in silico approach

IF 1.4 4区医学 Q4 BIOCHEMISTRY & MOLECULAR BIOLOGY Molecular and biochemical parasitology Pub Date : 2024-06-29 DOI:10.1016/j.molbiopara.2024.111646

Antônio Sérgio de Almeida Júnior , Mayse Manuele Freitas Viana Leal , Diego Santa Clara Marques , Anekécia Lauro da Silva , Rafael de Souza Bezerra , Yandra Flaviana Siqueira de Souza , Maria Eduardade Mendonça Silveira , Fábio AB Santos , Luiz Carlos Alves , André de Lima Aires , Iranildo José da Cruz Filho , Maria do Carmo Alves de Lima

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Abstract

The study aimed to conduct in vitro biological assessments of hydantoin and thiohydantoin compounds against mature Schistosoma mansoni worms, evaluate their cytotoxic effects and predict their pharmacokinetic parameters using computational methods. The compounds showed low in vitro cytotoxicity and were not considered hemolytic. Antiparasitic activity against adult S. mansoni worms was tested with all compounds at concentrations ranging from 200 to 6.25 μM. Compounds SC01, SC02, and SC03 exhibited low activity. Compounds SC04, SC05, SC06 and SC07 caused 100 % mortality within 24 h of incubation at a concentration of 100 and 200 μM. Thiohydantoin SC04 exhibited the highest activity, resulting in 100 % mortality after 24 h of incubation at a concentration of 50 μM and IC₅₀ of 28 µM. In the ultrastructural analysis (SEM), the compound SC04 (200 µM) induced integumentary changes, formation of integumentary blisters, and destruction of tubercles and spicules. Therefore, the SC04 compound shows promise as an antiparasitic against S. mansoni.

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海因和硫海因化合物对曼氏血吸虫的治疗潜力：综合体外、DNA、超微结构和 ADMET 的硅学方法。

该研究旨在针对成熟的曼氏血吸虫虫体对海因和硫代海因化合物进行体外生物学评估，评价其细胞毒性作用，并使用计算方法预测其药代动力学参数。这些化合物的体外细胞毒性较低，且不溶血。测试了所有化合物在 200 至 6.25μM 浓度范围内对曼氏成虫的抗寄生活性。化合物 SC01、SC02 和 SC03 的活性较低。浓度为 100 和 200μM 的化合物 SC04、SC05、SC06 和 SC07 在孵育 24 小时内造成 100%的死亡。硫代海因 SC04 的活性最高，当浓度为 50μM 和 IC50 为 28μM 时，培养 24 小时后死亡率为 100%。在超微结构分析（SEM）中，SC04 复合物（200µM）可诱导皮层变化，形成皮层水泡，破坏小瘤和棘突。因此，SC04 复合物有望成为曼氏沙门氏菌的抗寄生虫药。

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来源期刊

Molecular and biochemical parasitology 医学-寄生虫学

CiteScore

2.90

自引率

0.00%

发文量

审稿时长

63 days

期刊介绍： The journal provides a medium for rapid publication of investigations of the molecular biology and biochemistry of parasitic protozoa and helminths and their interactions with both the definitive and intermediate host. The main subject areas covered are: • the structure, biosynthesis, degradation, properties and function of DNA, RNA, proteins, lipids, carbohydrates and small molecular-weight substances • intermediary metabolism and bioenergetics • drug target characterization and the mode of action of antiparasitic drugs • molecular and biochemical aspects of membrane structure and function • host-parasite relationships that focus on the parasite, particularly as related to specific parasite molecules. • analysis of genes and genome structure, function and expression • analysis of variation in parasite populations relevant to genetic exchange, pathogenesis, drug and vaccine target characterization, and drug resistance. • parasite protein trafficking, organelle biogenesis, and cellular structure especially with reference to the roles of specific molecules • parasite programmed cell death, development, and cell division at the molecular level.