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

Abstract

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.

Clove Essential Oil (Syzygium aromaticum L. Myrtaceae): Extraction, Chemical Composition, Food Applications, and Essential Bioactivity for Human Health

“…Eugenol is a volatile compound that varies from colorless to light yellow and has low water solubility (approximately 2460 mg/L at 25 • C), a strong odor, and an intense flavor. Among the reported biological activities of eugenol are insecticidal, antimicrobial, anti-inflammatory, wound healing, antiviral, antioxidant, and anticancer activity [13,14,[23][24][25][26][27].…”

Tailored Functionalization of Natural Phenols to Improve Biological Activity

“…Numerous eugenol derivatives bearing triazole functionalities have been successfully accessed through the “click chemistry” approach ( Figure 4 , Scheme 18 ). Several examples are present in the literature about ( i ) O -alkylation of eugenol with terminal alkynes, followed by reaction with different benzyl azides [ 203 , 204 , 205 ]; ( ii ) eugenol conversion in epoxide and ring opening to obtain the corresponding alkyl azides, followed by reaction with different alkynes [ 206 ]; ( iii ) hydroboration oxidation at the allylic position of eugenol, followed by mesylation and azidation reactions, to achieve the eugenol azide; then, reaction with phenylacetylene to afford the triazole. Importantly, the first step of this latter process requires -OH protection trough silylation, thus allowing the synthesis of variously substituted products ( Scheme 18 ) [ 207 ].…”

“…Synthesized eugenol triazole derivatives showed leishmanicidal [ 205 ], antimycobacterial [ 207 ], trypanocidal [ 206 ], anticancer [ 203 ] as well as protease inhibitory [ 204 ] activity. Triazole eugenol glucosides also showed significant bactericidal activity and low toxicity to normal cells [ 208 ].…”

Clove Essential Oil (<em>Syzygium aromaticum L. Myrtaceae</em>): Extraction, Chemical Composition, Food Applications and Essential Bioactivities for Human Health

“…Eugenol is a volatile compound that varies from colorless to light yellow, has low water solubility (approximately 2460 mg/L at 25 °C), a strong odor, and an intense flavor. Among the reported biological activities of eugenol is insecticide activity, antimicrobial, anti-inflammatory, wound healing, antiviral, antioxidant, and anticancer [7,8,[14][15][16][17][18].…”

“…The CEO has shown antiviral activity against Ebola [101], influenza A virus [102], herpes simplex virus type 1, and type 2 [101]. Recent studies by de Oliveira et al showed that eugenol derivatives could inhibit the activity of the West Nile Virus, providing a promising compound against flaviviruses, such as dengue virus, Zika virus, and yellow fever virus [15]. Eugenol has also been studied as a possible inhibitor of the initial stage of infection by the HIV-1 virus because it can reduce virus replication.…”