Pinto-Martinez Andrea, Hernández-Rodríguez Vanessa, Rodríguez-Durán Jessica, Hejchman Elżbieta, Benaim Gustavo
Instituto de Estudios Avanzados (IDEA), Caracas, Venezuela.
Department of Organic Chemistry, Faculty of Pharmacy, Medical University of Warsaw, Warsaw, Poland.
Exp Parasitol. 2018 Jun;189:8-15. doi: 10.1016/j.exppara.2018.04.010. Epub 2018 Apr 11.
Chagas disease is a neglected tropical affection caused by the protozoan parasite Trypanosoma cruzi. There is no current effective treatment since the only two available drugs have a limited efficacy and produce side effects. Thus, investigation efforts have been directed to the identification of new drug leads. In this context, Ca regulating mechanisms have been postulated as targets for antiparasitic compounds, since they present paramount differences when compared to host cells. Amiodarone is an antiarrhythmic with demonstrated trypanocidal activity acting through the disruption of the parasite intracellular Ca homeostasis. We now report the effect of a benzofuran derivative based on the structure of amiodarone on T. cruzi. This derivative was able to inhibit the growth of epimastigotes in culture and of amastigotes inside infected cells, the clinically relevant phase. We also show that this compound, similarly to amiodarone, disrupts Ca homeostasis in T. cruzi epimastigotes, via two organelles involved in the intracellular Ca regulation and the bioenergetics of the parasite. We demonstrate that the benzofuran derivative was able to totally collapse the membrane potential of the unique giant mitochondrion of the parasite and simultaneously produced the alkalinization of the acidocalcisomes. Both effects are evidenced by a large increase in the intracellular Ca concentration of T. cruzi.
恰加斯病是一种由原生动物寄生虫克氏锥虫引起的被忽视的热带疾病。由于现有的仅有的两种药物疗效有限且会产生副作用，目前尚无有效的治疗方法。因此，研究工作一直致力于寻找新的药物先导物。在这种背景下，钙调节机制被认为是抗寄生虫化合物的作用靶点，因为与宿主细胞相比，它们存在显著差异。胺碘酮是一种抗心律失常药物，具有杀锥虫活性，可通过破坏寄生虫细胞内的钙稳态发挥作用。我们现在报告一种基于胺碘酮结构的苯并呋喃衍生物对克氏锥虫的作用。这种衍生物能够抑制培养中的无鞭毛体以及感染细胞内无鞭毛体（临床相关阶段）的生长。我们还表明，与胺碘酮类似，这种化合物通过参与寄生虫细胞内钙调节和生物能量学的两个细胞器破坏克氏锥虫无鞭毛体的钙稳态。我们证明，该苯并呋喃衍生物能够使寄生虫独特的巨大线粒体的膜电位完全崩溃，同时使酸性钙小体碱化。这两种效应都表现为克氏锥虫细胞内钙浓度大幅增加。
