A phthalimide-triazole derivative obtained by click chemistry exhibits trypanocidal activity, induces autophagy and ameliorates Trypanosoma cruzi infection

Abstract

Chagas disease (CD), caused by Trypanosoma cruzi, remains a leading cause of cardiomyopathy and heart failure in Latin America. Since the 1970s, benznidazole (BNZ) and nifurtimox (NFX) have been the only chemotherapeutic agents used to treat CD. However, their toxicity and low effectiveness in the chronic phase of the disease, make the development of more efficient chemotherapeutics imperative. Here, we investigated the effects of 1,2,3-triazole hybrids, synthesized via click chemistry, containing either phthalimide (FT1, FT2, FT3, FT4) or naphthoquinone (NT1) moieties on T. cruzi and their cytotoxicity on mammalian cells. NT1 and FT1 were the most effective against intracellular parasite with an IC₅₀ = 31.1 and 189.2 µM, respectively. FT1-FT4 showed low cytotoxicity to mammalian cells (CC₅₀ > 754 µM), while NT1 exhibited moderate toxicity (CC₅₀ ≥ 96.1 µM). FT1 demonstrated the highest selectivity towards trypomastigotes and amastigotes with selectivity indexes (SeI) of 6.9 and 6.7, respectively. Ultrastructural analysis of trypomastigotes treated with FT1 revealed mitochondrial alterations, lipid accumulation and Golgi complex disorganization. FT1 also decreased the mitochondrial membrane potential, increased mitochondrial reactive oxygen species (ROS) production, and induced late apoptosis in trypomastigotes. In infected cardiac cells, FT1 treatment led to degradation of amastigotes and Golgi disruption. An increase in autophagosomes in treated host cells and their interaction with intracellular parasites suggest that FT1-induced host cell autophagy may play a role in mitigating the infection and protecting cardiac cells from its deleterious effects.

Keywords: 1,2,3-Triazole; Autophagy; Chemotherapy; Click chemistry; Trypanosoma cruzi.