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Synthesis and Molecular Modeling of New 2-Benzylidenethiobarbituric Acid Derivatives As Potent Tyrosinase Inhibitors Agents Publisher



Najafi Z1 ; Kamarialiabadi A1 ; Sabourian R2 ; Hajimahmoodi M2 ; Chehardoli G3
Authors
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Authors Affiliations
  1. 1. Department of Medicinal Chemistry, School of Pharmacy, Hamadan University of Medical Sciences, Hamadan, Iran
  2. 2. Drug and Food Control Department, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
  3. 3. Department of Medicinal Chemistry, School of Pharmacy, Medicinal Plants and Natural Products Research Center, Hamadan University of Medical Sciences, Hamadan, Iran

Source: Journal of the Chinese Chemical Society Published:2022


Abstract

New 2-benzylidenethiobarbituric acid-(benzyloxyphenyl) derivatives were designed, synthesized, and evaluated as tyrosinase inhibitors. The products can be divided into two groups: 4-hydroxybenzaldehyde derivatives and vanillin derivatives. Some of the 4-hydroxybenzaldehyde derivatives showed significant inhibitory activity while all vanillin derivatives have no inhibitory activities. It seems that the presence of the methoxy group on the internal aromatic ring prevents the ligand–enzyme interaction. According to the tyrosinase inhibitory assay, 5-(4-([4-Methylbenzyl]oxy)benzylidene)-2-thioxodihydropyrimidine-4,6(1H,5H)-dione (4g) is the most potent antityrosinase agents with an IC50 value of 23.90 ± 0.08 μM. It showed even better inhibitory activity than kojic acid. The results of kinetic and molecular docking studies demonstrated that compound 4g acts as a noncompetitive inhibitor and can bind to some amino acids such as His263 and Val283 of the active site through Pi–alkyl and Pi–Pi interactions and areas around the active site via the hydrogen bond. In-silico adsorption, distribution, metabolism, excretion, and toxicity (ADMET) studies predicted that these products have good drug-likeness. All findings indicate the 2-benzylidenethiobarbituric acids with the benzyloxyphenyl tail have good potential for the treatment of melanogenesis compared to kojic acid. © 2022 The Chemical Society Located in Taipei & Wiley-VCH GmbH.