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Discovery of novel West Nile Virus protease inhibitor based on isobenzonafuranone and triazolic derivatives of eugenol and indan-1,3-dione scaffolds

2019; Public Library of Science; Volume: 14; Issue: 9 Linguagem: Inglês

10.1371/journal.pone.0223017

1932-6203

André Silva de Oliveira, Poliana Aparecida Rodrigues Gazolla, Ana Flávia C. da S. Oliveira, Wagner Luiz Pereira, Lívia Cristina de Souza Viol, Angélica Faleiros da Silva Maia, Edjon G. Santos, Ítalo Esposti Poly da Silva, Tiago Antônio de Oliveira Mendes, A.A. Silva, Roberto Sousa Dias, Cynthia Canêdo da Silva, Marcelo D. Polêto, Róbson Ricardo Teixeira, Sérgio Oliveira de Paula,

Trypanosoma species research and implications

The West Nile Virus (WNV) NS2B-NS3 protease is an attractive target for the development of therapeutics against this arboviral pathogen. In the present investigation, the screening of a small library of fifty-eight synthetic compounds against the NS2-NB3 protease of WNV is described. The following groups of compounds were evaluated: 3-(2-aryl-2-oxoethyl)isobenzofuran-1(3H)-ones; eugenol derivatives bearing 1,2,3-triazolic functionalities; and indan-1,3-diones with 1,2,3-triazolic functionalities. The most promising of these was a eugenol derivative, namely 4-(3-(4-allyl-2-methoxyphenoxy)-propyl)-1-(2-bromobenzyl)-1H-1,2,3-triazole (35), which inhibited the protease with IC50 of 6.86 μmol L-1. Enzyme kinetic assays showed that this derivative of eugenol presents competitive inhibition behaviour. Molecular docking calculations predicted a recognition pattern involving the residues His51 and Ser135, which are members of the catalytic triad of the WNV NS2B-NS3 protease.