Universidade Federal de Pernambuco (UFPE), Departamento de Química Fundamental, 50670-901, Recife, PE (Brazil); Fundação Oswaldo Cruz (Fiocruz), Centro de Pesquisas Gonçalo Moniz, CEP 40296-710, Salvador, BA (Brazil).
ChemMedChem. 2014 Jan;9(1):177-88. doi: 10.1002/cmdc.201300354. Epub 2013 Nov 7.
Pharmacological treatment of Chagas disease is based on benznidazole, which displays poor efficacy when administered during the chronic phase of infection. Therefore, the development of new therapeutic options is needed. This study reports on the structural design and synthesis of a new class of anti-Trypanosoma cruzi thiazolidinones (4 a-p). (2-[2-Phenoxy-1-(4-bromophenyl)ethylidene)hydrazono]-5-ethylthiazolidin-4-one (4 h) and (2-[2-phenoxy-1-(4-phenylphenyl)ethylidene)hydrazono]-5-ethylthiazolidin-4-one (4 l) were the most potent compounds, resulting in reduced epimastigote proliferation and were toxic for trypomastigotes at concentrations below 10 μM, while they did not display host cell toxicity up to 200 μM. Thiazolidinone 4 h was able to reduce the in vitro parasite burden and the blood parasitemia in mice with similar potency to benznidazole. More importantly, T. cruzi infection reduction was achieved without exhibiting mouse toxicity. Regarding the molecular mechanism of action, these thiazolidinones did not inhibit cruzain activity, which is the major trypanosomal protease. However, investigating the cellular mechanism of action, thiazolidinones altered Golgi complex and endoplasmic reticulum (ER) morphology, produced atypical cytosolic vacuoles, as well as induced necrotic parasite death. This structural design employed for the new anti-T. cruzi thiazolidinones (4 a-p) led to the identification of compounds with enhanced potency and selectivity compared to first-generation thiazolidinones. These compounds did not inhibit cruzain activity, but exhibited strong antiparasitic activity by acting as parasiticidal agents and inducing a necrotic parasite cell death.
克氏锥虫病的药物治疗基于苯并咪唑，在感染的慢性期使用时疗效不佳。因此，需要开发新的治疗选择。本研究报告了一类新的抗克氏锥虫噻唑烷酮（4a-p）的结构设计和合成。（2-[2-苯氧基-1-（4-溴苯基）亚乙基）腙]-5-乙基噻唑烷-4-酮（4h）和（2-[2-苯氧基-1-（4-苯基苯基）亚乙基）腙]-5-乙基噻唑烷-4-酮（4l）是最有效的化合物，导致增殖的滋养体减少，在低于 10μM 的浓度下对锥虫也有毒性，而在高达 200μM 的浓度下对宿主细胞没有毒性。噻唑烷酮 4h 能够降低体外寄生虫负荷和小鼠血液中的寄生虫血症，其效力与苯并咪唑相当。更重要的是，4h 能够减少寄生虫感染而不表现出小鼠毒性。关于作用的分子机制，这些噻唑烷酮不抑制克氏锥虫蛋白酶，即主要的锥虫蛋白酶。然而，在研究作用的细胞机制时，噻唑烷酮改变了高尔基体和内质网（ER）的形态，产生了非典型的胞质空泡，并诱导了坏死的寄生虫死亡。与第一代噻唑烷酮相比，这种针对新的抗克氏锥虫噻唑烷酮（4a-p）的结构设计导致了具有增强效力和选择性的化合物的鉴定。这些化合物不抑制克氏锥虫蛋白酶活性，但作为杀寄生虫剂发挥强大的抗寄生虫活性，并诱导坏死的寄生虫细胞死亡。
