Bithiophene derivative triggers multiple cell death pathways in Trypanosoma cruzi

Chagas disease, caused by the protozoan parasite Trypanosoma cruzi, remains the most impactful parasitic disease in Latin America and is now widespread worldwide. Despite several efforts in recent years, current drugs fall short of meeting the needs of endemic populations due to their high cost, toxicity, and resistance issues, creating an urgent need to discover and develop new therapeutic alternatives. Therefore, there is a pressing need to develop new drugs that are more effective, affordable, and specifically target the parasite. Thiophene derivatives have previously been described as having activity against trypanosomatids. In this study, we evaluate the ability of bithiophene 4-(5'-formyl-[2,2'-bithiophen]-5-yl)but-3-yn-1-yl acetate (BT-Ac) to act against the epimastigote, trypomastigote, and amastigote forms of Trypanosoma cruzi. BT-Ac exhibited activity against these parasitic forms at micromolar concentrations with IC₅₀/EC₅₀ values of 46.37, 75.98 and 115.19 μM against the respective life cycle stages and cytotoxicity of 573.04 μM on epithelial cells. The result of this activity was selectivity index of 12.36, 7.54 and 4.97 for parasites respectively, over mammalian cells and induction of cell death, such as apoptosis, autophagy and necrosis in parasites, through different pathways, with an emphasis on dysregulation in lipid metabolism. In epimastigotes, BT-Ac induced only apoptosis-like cell death, whereas in amastigotes, it induced both apoptosis-like and necrotic cell death. In trypomastigotes, all the previously mentioned mechanisms, along with autophagy, were caused by BT-Ac. Altogether, these results support the hypothesis that thiophene derivatives directly affect T. cruzi.