Machado Rayanne Regina Beltrame, Salvador Deysiane Lima, Gomes Carla Maria Beraldi, Bakoshi Amanda Beatriz Kawano, Ueda-Nakamura Tânia, de Oliveira Silva Sueli, Nakamura Celso Vataru, Sarragiotto Maria Helena, Lazarin-Bidóia Danielle
Laboratório de Inovação Tecnológica no Desenvolvimento de Fármacos e Cosméticos, Departamento de Ciências Básica da Saúde, Universidade Estadual de Maringá (UEM), Maringá, Brazil.
Programa de Pós-Graduação Em Química, Departamento de Química, Universidade Estadual de Maringá (UEM), Maringá, Brazil.
Chem Biol Drug Des. 2025 Aug;106(2):e70167. doi: 10.1111/cbdd.70167.
Leishmaniasis is one of the most important neglected tropical diseases, prevalent in underdeveloped or developing countries, and new pharmacological agents for this disease are urgently needed. In this study, thiophene derivatives based on the natural product 5'-methyl-(5-[4-acetoxy-1-butynyl])-2,2'-bithiophene were synthesized and evaluated against promastigote forms of Leishmania amazonensis. The bithiophene BT-1 was the most potent and selective synthetic compound toward the parasites, exhibiting IC of 23.2 μM against promastigotes and CC of 216.5 μM against macrophages, and its mechanism of action was determined through biochemical and ultrastructural analyses. An accumulation of lipid bodies, loss of cellular content, increased reactive oxygen species production and lipid peroxidation, damage to the plasma membrane, and mitochondrial depolarization were observed in BT-1-treated parasites. The results indicated that the death of L. amazonensis induced by BT-1 occurred via destabilizing the parasite's redox homeostasis. Our results also showed that the synthesis based on the natural compound scaffold consisted of useful strategies to obtain new synthetic antileishmanial compounds.
利什曼病是最重要的被忽视热带病之一，在不发达国家或发展中国家流行，因此迫切需要针对该疾病的新型药物。在本研究中，基于天然产物5'-甲基-(5-[4-乙酰氧基-1-丁炔基])-2,2'-联噻吩合成了噻吩衍生物，并对亚马逊利什曼原虫的前鞭毛体形式进行了评估。联噻吩BT-1是对寄生虫最有效且最具选择性的合成化合物，对前鞭毛体的IC50为23.2 μM，对巨噬细胞的CC50为216.5 μM，并通过生化和超微结构分析确定了其作用机制。在BT-1处理的寄生虫中观察到脂滴积累、细胞内容物丢失、活性氧产生增加和脂质过氧化、质膜损伤以及线粒体去极化。结果表明，BT-1诱导的亚马逊利什曼原虫死亡是通过破坏寄生虫的氧化还原稳态发生的。我们的结果还表明，基于天然化合物支架的合成是获得新型抗利什曼合成化合物的有用策略。
