Current treatment of Chagas disease (CD) is based on two substances, nifurtimox (NT) and benzonidazole (BZ), both considered unsatisfactory mainly due to their low activities and high toxicity profile. One of the main challenges faced in CD management concerns the identification of new drugs active in the acute and chronic phases and with good pharmacokinetic profiles. In this work, we studied the bioactivity of twenty 2-(1H-pyrazol-1-yl)-1,3,4-thiadiazole derivatives against Trypanosoma cruzi epimastigotes and trypomastigotes. We identified seven derivatives with promising activity against epimastigote forms with IC50 values ranging from 6 µM to 44 µM. Most of the compounds showed no significant toxicity against murine macrophages. Our initial investigation on the mechanism of action indicates that this series of compounds may exert their anti-parasitic effect, inducing cell membrane damage. The results in trypomastigotes showed that one derivative, PDAN 78, satisfactorily inhibited metabolic alteration at all concentrations. Moreover, we used molecular modeling to understand how tridimensional and structural aspects might influence the observed bioactivities. Finally, we also used in silico approaches to assess the potential pharmacokinetic and toxicological properties of the most active compounds. Our initial results indicate that this molecular scaffold might be a valuable prototype for novel and safe trypanocidal compounds.

目前恰加斯病 (CD) 的治疗基于硝呋替莫 (NT) 和苯硝唑 (BZ) 两种物质，这两种物质均因其低活性和高毒性而被认为不令人满意。 CD 管理面临的主要挑战之一是鉴定在急性期和慢性期具有活性且具有良好药代动力学特征的新药。在这项工作中，我们研究了二十种2-(1 H-吡唑-1-基)-1,3,4-噻二唑衍生物对克氏锥虫上鞭毛体和锥虫的生物活性。我们鉴定了七种对表鞭毛体形式具有良好活性的衍生物，其 IC50 值范围为 6 µM 至 44 µM。大多数化合物对小鼠巨噬细胞没有表现出明显的毒性。我们对作用机制的初步研究表明，这一系列化合物可能发挥其抗寄生虫作用，诱导细胞膜损伤。锥鞭毛体的结果表明，一种衍生物 PDAN 78 在所有浓度下都能令人满意地抑制代谢改变。此外，我们使用分子模型来了解三维和结构方面如何影响观察到的生物活性。最后，我们还使用计算机方法来评估最活跃化合物的潜在药代动力学和毒理学特性。我们的初步结果表明，这种分子支架可能是新型、安全的杀锥虫化合物的有价值的原型。