Synthesis, in vitro, and in silico studies of fisetin and quercetin and their metal complexes as inhibitors of α-glucosidase and thrombin

Abstract In this work, the inhibition mechanism of α-glucosidase and thrombin activity by fisetin and quercetin in coordination with metals (Fe and Zn) was investigated. Initially, the reactions between fisetin and quercetin with Fe(II) and Zn(II) and the resulting products were studied by UV-visible spectroscopy and mass spectrometry. Flavonoid−Fe/Zn complexes with a stoichiometry of 2:1 were successfully synthesized, and it was found that the apparent reaction constants of Fe(II) were larger than those of Zn(II), which was accompanied by the autoxidation of Fe(II) to Fe(III). Moreover, the fisetin/quercetin−Fe/Zn complexes inhibited α-glucosidase and thrombin activities by a mixed competitive approach. Among them, the quercetin−Fe complex showed the strongest inhibitory ability, with an IC50 of 0.08 ± 0.01 mM for α-glucosidase and 0.22 ± 0.04 mM for thrombin. Molecular simulations indicated that the fisetin/quercetin−Fe/Zn complexes could bind tightly to the active site and allosteric sites of α-glucosidase and thrombin. Van der Waals forces and hydrogen bonding were the major forces involved in the binding of the complexes to the enzymes. Metal coordination also had a crucial influence on the exertion of the inhibitory effect of flavonoids, especially the chelation of iron, which enhanced the electrostatic interaction of the fisetin/quercetin complexes with the enzyme.