Hyperuricemia (HUA), or elevated uric acid in the blood, has become more prevalent in recent years. Polyphenols, which are known to have good inhibitory activity on xanthine oxidoreductase (XOR), are effective in uric acid reduction. In this review, we address the structure–activity relationship of flavonoids that inhibit XOR activity from two perspectives: the key residues of XOR and the structural properties of flavonoids. Flavonoids’ inhibitory effect is enhanced by their hydroxyl, methoxy, and planar structures, whereas glycosylation dramatically reduces their activity. The flavonoid structure–activity relationship informed subsequent discussions of the changes that occur in polyphenols’ XOR inhibitory activity during their extraction, processing, gastrointestinal digestion, absorption, and interactions. Furthermore, gastrointestinal digestion and heat treatment during processing can boost the inhibition of XOR. Polyphenols with comparable structures may have a synergistic effect, and their synergy with allopurinol thus provides a promising future research direction.

Although α-amylase is crucial for postprandial glucose control, existing inhibitors present various side effects, necessitating the exploration of natural alternatives. The ability of sugarcane polyphenol (SP) to inhibit α-amylase remains unclear. This study assessed the inhibitory activity of SP via in vitro assays, circular dichroism (CD), fluorescence quenching, and stability analysis, while the mechanism of action was elucidated using molecular docking and molecular dynamics (MD). The results showed that the IC₅₀ of the SP was 0.841 ± 0.029 mg/mL, with proanthocyanidin-B1 (PC-B1) presenting the most potent effect (IC₅₀ = 0.504 ± 0.019 mg/mL). CD and barycentric mean (BCM) analysis indicated that the complexes might limit substrate binding. The mechanistic assessment showed that the polyphenols bonded to the active enzyme pockets to form stable complexes with reduced key residue fluctuations. In conclusion, SP, especially PC-B1, effectively inhibited α-amylase activity via structural regulation and molecular interactions, providing a theoretical basis for developing natural hypoglycemic agents.

This study systematically explored the inhibitory mechanisms against sucrase exerted by sugarcane molasses polyphenol extract (SMPE) and its three principal chlorogenic acid analogs: neochlorogenic acid (NA), chlorogenic acid (CA), and methyl chlorogenate (MC). By integrating in vitro assays, molecular simulations, and spectroscopic analyses, we demonstrated synergistic inhibition among the components. SMPE exhibited the greatest inhibitory potency (IC₅₀ = 3.58 ± 0.16 mg/mL), with an IC₅₀ significantly lower than those of the individual compounds. Synergy analysis indicated marked synergistic effects for both the CA-NA pair and the ternary mixture. Simultaneous multi-ligand docking further suggested complementary co-binding configurations and interactions with residues surrounding the catalytic region, providing a possible structural interpretation of the experimentally observed synergistic effects. Mechanistically, CA and NA exhibited competitive inhibition, whereas MC and SMPE showed mixed-type inhibition; fluorescence, CD, and thermal stability analyses revealed compound-dependent changes in aromatic residue microenvironments, secondary structure, and protein stability, while molecular modeling predicted peripheral binding of CA/NA and catalytic-region interactions of MC, suggesting distinct but complementary routes for perturbing substrate recognition and catalysis. This study provides mechanistic insight into the synergistic inhibition of sucrase by SMPE and supports its potential development as a natural agent for modulating postprandial glycemia.