Back to Search
Start Over
Targeting the subpocket in xanthine oxidase: Design, synthesis, and biological evaluation of 2-[4-alkoxy-3-(1H-tetrazol-1-yl) phenyl]-6-oxo-1,6-dihydropyrimidine-5-carboxylic acid derivatives
- Source :
- European Journal of Medicinal Chemistry. 181:111559
- Publication Year :
- 2019
- Publisher :
- Elsevier BV, 2019.
-
Abstract
- Xanthine oxidase is an important target for the treatment of hyperuricemia, gout and other related diseases. Analysis of the high-resolution structure of xanthine oxidase with febuxostat identified the existence of a subpocket formed by the residues Leu648, Asn768, Lys771, Leu1014 and Pro1076. In this study, we designed and synthesized a series of 2-[4-alkoxy-3-(1H-tetrazol-1-yl) phenyl]-6-oxo-1,6-dihydropyrimidine-5-carboxylic acid derivatives (8a-8z) with a tetrazole group targeting this subpocket of the xanthine oxidase active site, and they were further evaluated for their inhibitory potency against xanthine oxidase in vitro. The results showed that all the tested compounds (8a-8z) exhibited an apparent xanthine oxidase inhibitory potency, with IC50 values ranging from 0.0288 μM to 0.629 μM. Among them, compound 8u emerged as the most potent xanthine oxidase inhibitor, with an IC50 value of 0.0288 μM, which was comparable to febuxostat (IC50 = 0.0236 μM). The structure-activity relationship results revealed that the hydrophobic group at the 4′-position was indispensable for the inhibitory potency in vitro against xanthine oxidase. A Lineweaver-Burk plot revealed that the representative compound 8u acted as a mixed-type inhibitor for xanthine oxidase. Furthermore, molecular modeling studies were performed to gain insights into the binding mode of 8u with xanthine oxidase and suggested that the tetrazole group of the phenyl unit was accommodated in the subpocket, as expected. Moreover, a potassium oxonate-induced hyperuricemia model in rats was chosen to further confirm the hypouricemic effect of compound 8u, and the result demonstrated that compound 8u could effectively reduce serum uric acid levels at an oral dose of 5 mg/kg. In addition, acute oral toxicity study in mice indicated that compound 8u was nontoxic and tolerated at a dose up to 2000 mg/kg. Thus, compound 8u could be a potential and efficacious agent in treatment of hyperuricemia with low toxicity.
- Subjects :
- Male
Xanthine Oxidase
medicine.drug_class
Stereochemistry
Carboxylic acid
Carboxylic Acids
Mice, Inbred Strains
Hyperuricemia
01 natural sciences
Rats, Sprague-Dawley
Mice
Structure-Activity Relationship
03 medical and health sciences
chemistry.chemical_compound
Drug Discovery
medicine
Animals
Tetrazole
Enzyme Inhibitors
Xanthine oxidase
IC50
Xanthine oxidase inhibitor
030304 developmental biology
Pharmacology
chemistry.chemical_classification
0303 health sciences
Dose-Response Relationship, Drug
Molecular Structure
biology
010405 organic chemistry
Organic Chemistry
Active site
General Medicine
medicine.disease
Rats
0104 chemical sciences
Pyrimidines
chemistry
Drug Design
biology.protein
Female
Febuxostat
medicine.drug
Subjects
Details
- ISSN :
- 02235234
- Volume :
- 181
- Database :
- OpenAIRE
- Journal :
- European Journal of Medicinal Chemistry
- Accession number :
- edsair.doi.dedup.....bb790b9841f39a5a6807819b20e9f207