Alona V. Beiko

Xanthine oxidase is a known therapeutic target for the treatment of hyperuricemia and related diseases. Despite the availability of current drugs such as allopurinol and febuxostat, the search for new compounds to effectively inhibit this enzyme remains relevant. In our study, 75 virtual structures of 4‐(5‐aminosubstituted‐4‐cyanooxazol‐2‐yl)benzoic acids with structural similarity to febuxostat were designed for evaluation of their potency against xanthine oxidase. After molecular docking simulations, eight compounds were selected for synthesis and in vitro testing. The synthesized compounds were found to exhibit in vitro xanthine oxidase inhibitory activity in the nanomolar concentration range. The most effective inhibitors with 4‐benzylpiperidin‐1‐yl or 1,2,3,4‐tetrahydroisoquinolin‐2‐yl substituents at position 5 of the oxazole ring had IC₅₀ values close to that of febuxostat. The kinetic data suggest a mixed‐type inhibition when the inhibitor binds preferentially to the free enzyme rather than to the enzyme‐substrate complex. Molecular docking and molecular dynamic simulations were carried out to get insight into the key interactions of the inhibitors bound to the xanthine oxidase active site.

A series of rhodanine derivatives bearing 4-(furan-2-yl)benzoic acid moiety were synthesized and studied as inhibitors of xanthine oxidase. This enzyme is a known target for allopurinol and febuxostat used in the treatment of hyperuricemia, gout, and other diseases. The synthesized compounds with different substituents in position 3 of the rhodanine ring showed in vitro inhibitory activities towards xanthine oxidase in a low micromolar concentration range. The 4-(furan-2-yl)benzoic acid derivative with a fragment of N-unsubstituted rhodanine was found to have the lowest IC50 value which does not depend on the presence of albumin or Tween-80 under the assay conditions. According to kinetic data, the rhodanine-based 4-(furan-2-yl)benzoic acid was a mixed-type inhibitor with the same affinity for the free enzyme and the enzyme-substrate complex. Molecular docking and molecular dynamic studies were performed to elucidate the binding mode of this compound in the active site of xanthine oxidase

The pyrazolone-based 4-(furan-2-yl)benzoic acids have been synthesized and studied as xanthine oxidase inhibitors. This enzyme is one of the therapeutic targets for the treatment of hyperuricemia and related diseases. The compounds studied have found to exhibit low micromolar IC50 values relative to the enzyme in vitro, depending on substituents in position 3 of the pyrazolone ring. However, the inhibitory effects observed are reduced in the presence of bovine serum albumin or Tween-80. Among the pyrazolone derivatives synthesized, 4-(5-((3-methyl-5-oxo-1-phenyl-1,5-dihydro-4H-pyrazol-4-ylidene)methyl)furan-2-yl)benzoic acid has been found to be the most potent inhibitor of xanthine oxidase. Kinetic results have shown that this compound is a mixed-type inhibitor with higher affinity to the free enzyme than to the enzyme-substrate complex. The results of the molecular docking and molecular dynamics show that the carboxylic group of the inhibitor can form a salt bridge with Arg880 and a hydrogen bond with Thr1010. These interactions can be key factors in the enzyme-inhibitor complex stabilization.

Aurone derivatives possessing a wide range of biological activities are of high interest in medicinal chemistry. Carboxylated aurones were found previously to inhibit xanthine oxidase, which is a potential target for treatment of hyperuricemia and gout. In this paper, a series of B-ring nitro-substituted aurone derivatives were studied in vitro as inhibitors of this enzyme. The introduction of hydroxyl group into the B-ring of nitro-functionalized aurones resulted in significant increase of their inhibitory potency. At the same time, aurones chlorinated at ring A and containing nitro and hydroxyl groups at ring B showed only slightly increased inhibition effect. The kinetic studies and molecular docking calculations were carried out to explain the inhibition mechanism of xanthine oxidase by the nitro-substituted aurone derivatives