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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

[ Vol. 15 , Issue. 3 ]

Author(s):

Bianca N. M. Silva, Policarpo A. Sales , Alvaro J. Romanha, Silvane M. F. Murta, Camilo H. S. Lima, Magaly G. Albuquerque, Eliane D'Elia, Jose G. de Aquino, Vitor F. Ferreira, Fernando C. Silva, Angelo C. Pinto and Barbara V. Silva*   Pages 240 - 256 ( 17 )

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.

Keywords:

Chagas disease, Trypanosoma cruzi, 1, 2, 3-triazole, isatin, thiosemicarbazone, semicarbazone, trypanocidal.

Affiliation:

Instituto de Quimica (IQ), Universidade Federal do Rio de Janeiro (UFRJ), Av. Athos da Silveira Ramos, 149, Cidade Universitária, Ilha do Fundão, 21949-900, Rio de Janeiro, RJ, Centro de Pesquisas Rene Rachou (CPqRR), Fundacao Oswaldo Cruz (FIOCRUZ), Av. Augusto de Lima, 1715, Barro Preto, 30190-002, Belo Horizonte, MG, Centro de Pesquisas Rene Rachou (CPqRR), Fundacao Oswaldo Cruz (FIOCRUZ), Av. Augusto de Lima, 1715, Barro Preto, 30190-002, Belo Horizonte, MG, Centro de Pesquisas Rene Rachou (CPqRR), Fundacao Oswaldo Cruz (FIOCRUZ), Av. Augusto de Lima, 1715, Barro Preto, 30190-002, Belo Horizonte, MG, Faculdade de Farmacia (FF), Universidade Federal Fluminense (UFF), R. Mário Viana, 523, Santa Rosa, 24241-000, Niterói, RJ, Instituto de Quimica (IQ), Universidade Federal do Rio de Janeiro (UFRJ), Av. Athos da Silveira Ramos, 149, Cidade Universitária, Ilha do Fundão, 21949-900, Rio de Janeiro, RJ, Instituto de Quimica (IQ), Universidade Federal do Rio de Janeiro (UFRJ), Av. Athos da Silveira Ramos, 149, Cidade Universitária, Ilha do Fundão, 21949-900, Rio de Janeiro, RJ, Instituto de Quimica (IQ), Universidade Federal do Rio de Janeiro (UFRJ), Av. Athos da Silveira Ramos, 149, Cidade Universitária, Ilha do Fundão, 21949-900, Rio de Janeiro, RJ, Instituto de Quimica (IQ), Universidade Federal Fluminense (UFF), 24020-141 Niterói, RJ, Instituto de Quimica (IQ), Universidade Federal Fluminense (UFF), 24020-141 Niterói, RJ, Instituto de Quimica (IQ), Universidade Federal do Rio de Janeiro (UFRJ), Av. Athos da Silveira Ramos, 149, Cidade Universitária, Ilha do Fundão, 21949-900, Rio de Janeiro, RJ, Instituto de Quimica (IQ), Universidade Federal do Rio de Janeiro (UFRJ), Av. Athos da Silveira Ramos, 149, Cidade Universitária, Ilha do Fundão, 21949-900, Rio de Janeiro, RJ



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