Silva Bianca N M, Sales Junior Policarpo A, Romanha Alvaro J, Murta Silvane M F, Lima Camilo H S, Albuquerque Magaly G, D'Elia Eliane, Rodrigues José G A, Ferreira Vitor F, Silva Fernando C, Pinto Angelo C, Silva Bárbara V
Instituto de Quimica (IQ), Universidade Federal do Rio de Janeiro (UFRJ), Av. Athos da Silveira Ramos, 149, Cidade Universitaria, Ilha do Fundao, 21949-900, Rio de Janeiro, RJ, Brazil.
Centro de Pesquisas Rene Rachou (CPqRR), Fundacao Oswaldo Cruz (FIOCRUZ), Av. Augusto de Lima, 1715, Barro Preto, 30190-002, Belo Horizonte, MG, Brazil.
Med Chem. 2019;15(3):240-256. doi: 10.2174/1573406414666180912120502.
Chagas disease, also known as American trypanosomiasis, is classified as one of the 17 most important neglected diseases by the World Health Organization. The only drugs with proven efficacy against Chagas disease are benznidazole and nifurtimox, however both show adverse effects, poor clinical efficacy, and development of resistance. For these reasons, the search for new effective chemical entities is a challenge to research groups and the pharmaceutical industry.
Synthesis and evaluation of antitrypanosomal activities of a series of thiosemicarbazones and semicarbazones containing 1,2,3-1H triazole isatin scaffold.
5'-(4-alkyl/aryl)-1H-1,2,3-triazole-isatins were prepared by Huisgen 1,3-dipolar cycloaddition and the thiosemicarbazones and semicarbazones were obtained by the 1:1 reactions of the carbonylated derivatives with thiosemicarbazide and semicarbazide hydrochloride, respectively, in methanol, using conventional reflux or microwave heating. The compounds were assayed for in vitro trypanocidal activity against Trypanosoma cruzi, the aetiological agent of Chagas disease. Beyond the thio/semicarbazone derivatives, isatin and triazole synthetic intermediates were also evaluated for comparison.
A series of compounds were prepared in good yields. Among the 37 compounds evaluated, 18 were found to be active, in particular thiosemicarbazones containing a non-polar saturated alkyl chain (IC50 = 24.1, 38.6, and 83.2 µM; SI = 11.6, 11.8, and 14.0, respectively). To further elucidate the mechanism of action of these new compounds, the redox behaviour of some active and inactive derivatives was studied by cyclic voltammetry. Molecular docking studies were also performed in two validated protein targets of Trypanosoma cruzi, i.e., cruzipain (CRZ) and phosphodiesterase C (TcrPDEC).
A class of thio/semicarbazones structurally simple and easily accessible was synthesized. Compounds containing thiosemicarbazone moieties showed the best results in the series, being more active than the corresponding semicarbazones. Our results indicated that the activity of these compounds does not originate from an oxidation-reduction pathway but probably from the interactions with trypanosomal enzymes.
恰加斯病，又称美洲锥虫病，被世界卫生组织列为17种最重要的被忽视疾病之一。唯一被证实对恰加斯病有效的药物是苯硝唑和硝呋替莫，然而这两种药物都有不良反应、临床疗效不佳且会产生耐药性。由于这些原因，寻找新的有效化学实体对研究团队和制药行业来说是一项挑战。
合成并评估一系列含有1,2,3-1H三唑异吲哚骨架的硫代氨基脲和氨基脲的抗锥虫活性。
通过惠斯根1,3-偶极环加成反应制备5'-(4-烷基/芳基)-1H-1,2,3-三唑异吲哚，硫代氨基脲和氨基脲分别通过羰基化衍生物与硫代氨基脲和盐酸氨基脲在甲醇中以1:1的比例反应制得，采用常规回流或微波加热。对这些化合物进行了针对恰加斯病病原体克氏锥虫的体外杀锥虫活性测定。除了硫代/氨基脲衍生物外，还对异吲哚和三唑合成中间体进行了评估以作比较。
以良好的产率制备了一系列化合物。在评估的37种化合物中，发现18种具有活性，特别是含有非极性饱和烷基链的硫代氨基脲（IC50分别为24.1、38.6和83.2 μM；SI分别为11.6、11.8和14.0）。为了进一步阐明这些新化合物的作用机制，通过循环伏安法研究了一些活性和非活性衍生物的氧化还原行为。还对克氏锥虫的两个经过验证的蛋白质靶点，即克氏锥虫蛋白酶（CRZ）和磷酸二酯酶C（TcrPDEC）进行了分子对接研究。
合成了一类结构简单且易于获得的硫代/氨基脲。含有硫代氨基脲部分的化合物在该系列中显示出最佳结果，比相应的氨基脲更具活性。我们的结果表明，这些化合物的活性并非源于氧化还原途径，而是可能源于与锥虫酶的相互作用。
