Design, synthesis and biological evaluation of N-(4-alkoxy-3-(1H-tetrazol-1-yl)phenyl) heterocyclic aromatic amide derivatives as xanthine oxidase inhibitors.
Bioorg Chem
; 127: 105938, 2022 10.
Article
em En
| MEDLINE
| ID: mdl-35752100
ABSTRACT
Xanthine oxidase (XO) is a flavoprotein that exists in various organisms and can catalyze the uric acid formation in the human body. Based on the amide framework of N-(4-((3-cyanobenzyl)oxy)-3-(1H-tetrazol-1-yl)phenyl)isonicotinamide (compound 1) reported in our previous work, a series of N-(4-alkoxy-3-(1H-tetrazol-1-yl)phenyl) heterocyclic aromatic amide derivatives were designed, synthesized and evaluated as novel amide-based XO inhibitors. Structure-activity relationship campaign identified the most promising compound g25 (IC50 = 0.022 µM), which possesses a special 1H-imidazole-5-carboxamide scaffold and presented comparable XO inhibitory potency to topiroxostat (IC50 = 0.017 µM). Enzyme kinetic studies revealed that compound g25 acted as a mixed-type XO inhibitor. Molecular docking and molecular dynamics indicated that imidazole NH of g25 formed two stable hydrogen bonds with Glu1261 residue of XO that provided a vital contribution for the binding affinity. In addition, in vivo activity evaluation demonstrated that compound g25 exhibited obviously hypouricemic effect on a potassium oxonate induced hyperuricemic rat model.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Xantina Oxidase
/
Amidas
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article