Lucas Eduardo Bezerra de Lima , Maria Letícia Gomes de Almeida , Gleicyane Silva Gomes , Pedro Henrique do Nascimento , Carla Jasmine Oliveira e Silva , Cecilãne Regina Dioclecia da Silva , Yuri Mouzinho Ramos Tanaka , Tatiany Patrícia Romão , Thaíses Brunelle Santana de Lima , Elmo Silvano de Araújo , Patricia Lopes Barros de Araújo , Paulo Euzébio Cabral Filho , Vanderlan Nogueira Holanda , Ronaldo Nascimento de Oliveira , Regina Celia Bressan Queiroz de Figueiredo
{"title":"A phthalimide-triazole derivative obtained by click chemistry exhibits trypanocidal activity, induces autophagy and ameliorates Trypanosoma cruzi infection","authors":"Lucas Eduardo Bezerra de Lima , Maria Letícia Gomes de Almeida , Gleicyane Silva Gomes , Pedro Henrique do Nascimento , Carla Jasmine Oliveira e Silva , Cecilãne Regina Dioclecia da Silva , Yuri Mouzinho Ramos Tanaka , Tatiany Patrícia Romão , Thaíses Brunelle Santana de Lima , Elmo Silvano de Araújo , Patricia Lopes Barros de Araújo , Paulo Euzébio Cabral Filho , Vanderlan Nogueira Holanda , Ronaldo Nascimento de Oliveira , Regina Celia Bressan Queiroz de Figueiredo","doi":"10.1016/j.biopha.2025.117963","DOIUrl":null,"url":null,"abstract":"<div><div>Chagas disease (CD), caused by <em>Trypanosoma cruzi,</em> 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 <em>via</em> click chemistry, containing either phthalimide (<strong>FT1</strong>, <strong>FT2</strong>, <strong>FT3, FT4)</strong> or naphthoquinone (<strong>NT1</strong>) moieties on <em>T. cruzi</em> and their cytotoxicity on mammalian cells. <strong>NT1</strong> and <strong>FT1</strong> were the most effective against intracellular parasite with an IC<sub>50</sub> = 31.1 and 189.2 µM, respectively. <strong>FT1</strong>-<strong>FT4</strong> showed low cytotoxicity to mammalian cells (CC<sub>50</sub> > 754 µM), while <strong>NT1</strong> exhibited moderate toxicity (CC<sub>50</sub> ≥ 96.1 µM). <strong>FT1</strong> 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 <strong>FT1</strong> revealed mitochondrial alterations, lipid accumulation and Golgi complex disorganization. <strong>FT1</strong> also decreased the mitochondrial membrane potential, increased mitochondrial reactive oxygen species (ROS) production, and induced late apoptosis in trypomastigotes. In infected cardiac cells, <strong>FT1</strong> 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 <strong>FT1</strong>-induced host cell autophagy may play a role in mitigating the infection and protecting cardiac cells from its deleterious effects.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"186 ","pages":"Article 117963"},"PeriodicalIF":6.9000,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Biomedicine & Pharmacotherapy","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S075333222500157X","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"MEDICINE, RESEARCH & EXPERIMENTAL","Score":null,"Total":0}
引用次数: 0
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.
期刊介绍:
Biomedicine & Pharmacotherapy stands as a multidisciplinary journal, presenting a spectrum of original research reports, reviews, and communications in the realms of clinical and basic medicine, as well as pharmacology. The journal spans various fields, including Cancer, Nutriceutics, Neurodegenerative, Cardiac, and Infectious Diseases.