Synthesis, structure-activity relationships, and mechanistic studies of 5-arylazo-tropolone derivatives as novel xanthine oxidase (XO) inhibitors.
Bioorg Med Chem
; 26(2): 536-542, 2018 01 15.
Article
em En
| MEDLINE
| ID: mdl-29274704
ABSTRACT
Xanthine oxidase (XO) is an enzyme that contains molybdenum at the active site and catalyzes the oxidation of purine bases to uric acid. Even though XO inhibitors are widely used for the treatment of hyperuricemia and gout, only very few such compounds are clinically used as drugs for the treatment of these diseases. Given the unique physicochemical properties of tropolone, i.e., its chelating effect and the pKa value that is similar to that of carboxylic acid, we have synthesized 22 5-arylazotropolone derivatives as potential XO inhibitors. In vitro enzyme-inhibitory assays for XO revealed that 3-nitro derivative 1j showed the most potent XO inhibitory activity, which is by one order of magnitude more potent than allopurinol. An enzyme-kinetic study revealed that 1j inhibited the production of uric acid by XO both competitively and non-competitively. A docking-simulation study of 1j with XO suggested that the carbonyl and hydroxyl groups of the tropolone ring interact with the hydroxy group that acts as a ligand for molybdenum and the amino acid residues around the active site of XO.
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Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Tropolona
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Xantina Oxidase
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Inibidores Enzimáticos
Limite:
Animals
Idioma:
En
Ano de publicação:
2018
Tipo de documento:
Article