Hydroxyalkyne–Bithiophene Derivatives: Synthesis and Antileishmanial Activity

Abstract

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 IC₅₀ of 23.2 μM against promastigotes and CC₅₀ 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.