Synthesis and structure-activity relationship analysis of 2-substituted-1,2,4-triazolo[1,5-a]pyrimidin-7-ones and their 6-carboxylate derivatives as xanthine oxidase inhibitors.

Abstract

Hyperuricemia is characterised by high blood levels of uric acid, and it can degenerate into gout when monosodium urate crystals precipitate in joints and other tissues. Uric acid is produced during the catabolism of xanthine by the enzyme xanthine oxidase (XO), which is the primary therapeutic target in gout treatment. Current XO inhibitors approved to treat gout, such as allopurinol and febuxostat, suffer from serious adverse effects, creating the need for new drug molecules. Three libraries comprising 75 purine analogues were designed using a 1,2,4-triazolo[1,5-a]pyrimidine scaffold, synthesised and tested in vitro as potential XO inhibitors. The screening identified that 23 compounds exhibited better inhibitory activity than allopurinol, with 2-(4-isopropoxyphenyl)-7-oxo-4,7-dihydro-1,2,4-triazolo[1,5-a]pyrimidine-6-carboxylic acid being 23 times more potent. Enzyme kinetics studies and molecular docking simulations were performed on the most active compounds to identify the mechanism of action and intermolecular interactions between the active site of XO and the inhibitors. The most potent compounds exhibited a mix-type inhibition mechanism and were predicted to interact with the same amino acid residues as allopurinol. These novel purine analogues are promising hits for further new lead development among purine-like drug XO inhibitors with therapeutic potential in the treatment of hyperuricemia and associated diseases.