ABSTRACT
Tyrosinase is a multifunctional, glycosylated and copper-containing oxidase enzyme that can be found in animals, plants, and fungi. It is involved in several biological processes such as melanin biosynthesis. In this work, a series of isobenzofuran-1(3H)-ones was evaluated as tyrosinase inhibitors. It was found that compounds phthalaldehydic acid (1), 3-(2,6-dihydroxy-4-isopropylphenyl)isobenzofuran-1(3H)-one (7), and 2-(3-oxo-1,3-dihydroisobenzofuran-1-yl)-1,3-phenylene diacetate (9) were the most potent compounds inhibiting tyrosinase activity in a concentration dependent manner. Ligand-enzyme NMR studies and docking investigations allowed to map the atoms of the ligands involved in the interaction with the copper atoms present in the active site of the tyrosinase. This behaviour is similar to kojic acid, a well know tyrosinase inhibitor and used as positive control in the biological assays. The findings herein described pave the way for future rational design of new tyrosinase inhibitors.
Subject(s)
Benzofurans/chemistry , Copper/chemistry , Enzyme Inhibitors/chemistry , Monophenol Monooxygenase/chemistry , Structure-Activity Relationship , Catalytic Domain/drug effects , Enzyme Inhibitors/pharmacology , Ligands , Molecular Docking Simulation , Molecular Structure , Monophenol Monooxygenase/antagonists & inhibitors , Nuclear Magnetic Resonance, BiomolecularABSTRACT
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.
Subject(s)
Antiviral Agents/pharmacology , Endopeptidases/metabolism , Protease Inhibitors/pharmacology , Viral Nonstructural Proteins/antagonists & inhibitors , West Nile virus/enzymology , Antiviral Agents/chemistry , Catalytic Domain/drug effects , Drug Discovery , Endopeptidases/chemistry , Eugenol/chemistry , Histidine/chemistry , Histidine/metabolism , Indans/chemistry , Inhibitory Concentration 50 , Molecular Docking Simulation , Protease Inhibitors/chemistry , Serine/chemistry , Serine/metabolism , Structure-Activity Relationship , Viral Nonstructural Proteins/chemistryABSTRACT
Isobenzofuran-1(3H)-ones (phtalides) are heterocycles that present a benzene ring fused to a γ-lactone functionality. This structural motif is found in several natural and synthetic compounds that present relevant biological activities. In the present investigation, the 3-(2-hydroxy-4,4-dimethyl-6-oxocyclohexen-1-yl)isobenzofuran-1(3H)-one was characterized by single-crystal X-ray analysis. In the crystal structure, there are two molecules per asymmetric unit. One of them exhibits resonance assisted hydrogen bonds (RAHBs). Semi-empirical and DFT calculations were performed to obtain electronic structure and π-delocalization parameters, in order to better understand the energy stabilization of RAHBs in the crystal packing of the studied molecule. The structural parameters showed good agreement between theoretical and experimental data. The theoretical investigation revealed that the RAHBs stabilization energy is directly related to the electronic delocalization of the enol form fragment. In addition, RAHBs significantly affected the HOMO and charge distribution around the conjugated system.
