Synthesis of New Thiosemicarbazones and Semicarbazones Containing the 1,2,3-1H-triazole-isatin Scaffold: Trypanocidal, Cytotoxicity, Electrochemical Assays, and Molecular Docking

Abstract

Background: 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. Objective: Synthesis and evaluation of antitrypanosomal activities of a series of thiosemicarbazones and semicarbazones containing 1,2,3-1H triazole isatin scaffold. Method: 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. Results: 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). Conclusion: 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.

Análise quimiométrica de seletividade nos sítios ativos de cisteíno proteases da família da papaína para o estudo de substâncias antiparasitárias e antineoplásicas

“…Gráfico de barras relacionando-se o RMSD entre as estruturas redocadas com os programas HYBRID e FRED e os respectivos ligantes cognatos.Notas: Curva azul refere-se ao programa FRED, curva vermelha refere-se ao programa HYBRID. Fonte: autoria própria.Os valores em sua maioria estão abaixo de 2 Å (valor usualmente aceito como bom239 ) e os dois algoritmos obtiveram resultado similar. Como o programa HYBRID utiliza-se de informações do ligante cristalizado, decidiu-se por utilizar o programa FRED na docagem realizada no conjunto de inibidores do filtro virtual, pois este apresenta um espaço químico mais amplo nos substituintes P1, P2 e P3 que o conjunto de ligantes dipeptidil nitrilas cocristalizadas com o grupo de proteínas do trabalho, utilizado como base de dados no experimento de redocagem.4.5 Docagem do conjunto de inibidores do filtro virtualO valor de corte para K i para a seleção dos compostos foi considerado como 100 nM (ou pK i > 7) com relação às enzimas estudadas (CatB, CatK, CatL, CatS e Cz) pois assim seria considerado somente um conjunto de inibidor com elevada potência para a enzima alvo.Após considerar a potência, selecionou-se as estruturas que continham a nitrila como grupo reativo e que tivessem estrutura do tipo dipeptídica, ou seja, compostos miméticos de dipeptidil nitrilas.…”