In silico design and synthesis of hesperitin derivatives as new xanthine oxidase inhibitors

BACKGROUND: Hesperitin, a naturally occurring flavonoid was hybridized with phenolic acids to evaluate its potential to inhibit the activity of xanthine oxidase (XO), a key enzyme which catalyses xanthine to uric acid which is found to be associated with gout and many life style related disorders. OBJECTIVE: To develop new xanthine oxidase inhibitors from natural constituents along with antioxidant potential. METHOD: In this report, we designed and synthesized hesperitin derivatives hybridized with natural phenolic acids to form ester linkage with the help of molecular docking. The synthesized compounds were evaluated for their antioxidant and xanthine oxidase inhibitory potential. RESULTS: The in vitro xanthine oxidase inhibitory activity and enzyme kinetics studies showed that hesperitin derivatives displayed a potential inhibition against XO in competitive manner with IC(50) value ranging from 9.0 to 23.15 µM and HET4 was revealed as most active derivative. Molecular simulation revealed that new hesperitin derivatives interacted with the amino acid residues SER1080, PHE798, GLN1194, ARG912, THR1083, ALA1078 and MET1038 located within the active cavity of XO. Results of antioxidant activity revealed that all the derivatives showed very good antioxidant potential. CONCLUSION: Taking advantage of molecular docking, this hybridization of two natural constituent could lead to desirable xanthine oxidase inhibitors with improved activity.