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2100-01-01
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SYNTHESIS OF NEW THIOSEMICARBAZONES AND SEMICARBAZONES CONTAINING THE 1,2,3-1H-TRIAZOLE-ISATIN SCAFFOLD: TRYPANOCIDAL, CYTOTOXICITY, ELECTROCHEMICAL ASSAYS, AND MOLECULAR DOCKING
Chagas disease
Trypanosoma cruzi
Isatin
semicarbazone
Thiosemicarbazone
Trypanocidal
Author
Silva, Bianca Nascimento Monteiro da
Sales Junior, Policarpo Ademar
Romanha, Alvaro Jose
Murta, Silvane Maria Fonseca
Lima, Camilo Henrique da Silva
Albuquerque, Magaly Girão
D'Elia, Eliane
Rodrigues, José G. A.
Ferreira, Vitor Francisco
Silva, Fernando de Carvalho da
Pinto, Angelo da Cunha
Silva, Barbara Vasconcellos da
Sales Junior, Policarpo Ademar
Romanha, Alvaro Jose
Murta, Silvane Maria Fonseca
Lima, Camilo Henrique da Silva
Albuquerque, Magaly Girão
D'Elia, Eliane
Rodrigues, José G. A.
Ferreira, Vitor Francisco
Silva, Fernando de Carvalho da
Pinto, Angelo da Cunha
Silva, Barbara Vasconcellos da
Affilliation
Universidade Federal do Rio de Janeiro. Instituto de Química. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Rene Rachou. Belo Horizonte, MG, Brasil.
Fundação Oswaldo Cruz. Instituto Rene Rachou. Belo Horizonte, MG, Brasil.
Fundação Oswaldo Cruz. Instituto Rene Rachou. Belo Horizonte, MG, Brasil.
Universidade Federal Fluminense. Faculdade de Farmácia. Rio de Janeiro, RJ, Brasil.
Universidade Federal do Rio de Janeiro. Instituto de Química. Rio de Janeiro, RJ, Brasil.
Universidade Federal do Rio de Janeiro. Instituto de Química. Rio de Janeiro, RJ, Brasil.
Universidade Federal Fluminense. Instituto de Química. Rio de Janeiro, RJ, Brasil.
Universidade Federal Fluminense. Instituto de Química. Rio de Janeiro, RJ, Brasil.
Universidade Federal Fluminense. Instituto de Química. Rio de Janeiro, RJ, Brasil.
Universidade Federal do Rio de Janeiro. Instituto de Química. Rio de Janeiro, RJ, Brasil.
Universidade Federal do Rio de Janeiro. Instituto de Química. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Rene Rachou. Belo Horizonte, MG, Brasil.
Fundação Oswaldo Cruz. Instituto Rene Rachou. Belo Horizonte, MG, Brasil.
Fundação Oswaldo Cruz. Instituto Rene Rachou. Belo Horizonte, MG, Brasil.
Universidade Federal Fluminense. Faculdade de Farmácia. Rio de Janeiro, RJ, Brasil.
Universidade Federal do Rio de Janeiro. Instituto de Química. Rio de Janeiro, RJ, Brasil.
Universidade Federal do Rio de Janeiro. Instituto de Química. Rio de Janeiro, RJ, Brasil.
Universidade Federal Fluminense. Instituto de Química. Rio de Janeiro, RJ, Brasil.
Universidade Federal Fluminense. Instituto de Química. Rio de Janeiro, RJ, Brasil.
Universidade Federal Fluminense. Instituto de Química. Rio de Janeiro, RJ, Brasil.
Universidade Federal do Rio de Janeiro. Instituto de Química. Rio de Janeiro, RJ, Brasil.
Universidade Federal do Rio de Janeiro. Instituto de Química. Rio de Janeiro, RJ, Brasil.
Abstract
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.
Keywords
1,2,3-triazoleChagas disease
Trypanosoma cruzi
Isatin
semicarbazone
Thiosemicarbazone
Trypanocidal
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