Background: Xanthine oxidase (XO; EC 220.127.116.11) has been considered as a potent drug
target for the cure and management of pathological conditions prevailing due to high levels of uric
acid in the bloodstream. The role of xanthine oxidase has been well established in the generation
of hyperuricemia and gout due to its important role in catalytic oxidative hydroxylation of hypoxanthine
to xanthine and further catalyses of xanthine to generate uric acid. In this research, syringic
acid, a bioactive phenolic acid was explored to determine the capability of itself and its derivatives
to inhibit xanthine oxidase.
Objective: The study aimed to develop new xanthine oxidase inhibitors from natural constituents
along with the antioxidant potential.
Methods: In this report, we designed and synthesized syringic acid derivatives hybridized with alcohol
and amines to form ester and amide linkage with the help of molecular docking. The synthesized
compounds were evaluated for their antioxidant and xanthine oxidase inhibitory potential.
Results: Results of the study revealed that SY3 produces very good xanthine oxidase inhibitory
activity. All the compounds showed very good antioxidant activity. The enzyme kinetic studies
performed on syringic acid derivatives showed a potential inhibitory effect on XO ability in a
competitive manner with IC50 value ranging from 07.18μM-15.60μM and SY3 was revealed as the
most active derivative. Molecular simulation revealed that new syringic acid derivatives interacted
with the amino acid residues SER1080, PHE798, GLN1194, ARG912, GLN 767, ALA1078 and
MET1038 positioned inside the binding site of XO. Results of antioxidant activity revealed that all
the derivatives showed very good antioxidant potential.
Conclusion: Molecular docking proved to be an effective and selective tool in the design of new
syringic acid derivatives .This hybridization of two natural constituents could lead to desirable
xanthine oxidase inhibitors with improved activity.