Hydroxylated chalcones with dual properties: Xanthine oxidase inhibitors and radical scavengers

• Synthesized 20 chalcones by Claisen–Schmidt condensation reactions.
• Determined inhibitory potencies of chalcones against activity of xanthine oxidase.
• Performed molecular docking and identified critical enzyme/inhibitor interactions.
• Measured abilities of chalcones to scavenge a stable radical.
• Established structure–activity relationships for inhibition and scavenging measured the protective effect of chalcones on neurons exposed to β-amyloid peptide.

In this study, we evaluated the abilities of a series of chalcones to inhibit the activity of the enzyme xanthine oxidase (XO) and to scavenge radicals. 20 mono- and polyhydroxylated chalcone derivatives were synthesized by Claisen–Schmidt condensation reactions and then tested for inhibitory potency against XO, a known generator of reactive oxygen species (ROS). In parallel, the ability of the synthesized chalcones to scavenge a stable radical was determined. Structure–activity relationship analysis in conjunction with molecular docking indicated that the most active XO inhibitors carried a minimum of three hydroxyl groups. Moreover, the most effective radical scavengers had two neighboring hydroxyl groups on at least one of the two phenyl rings. Since it has been proposed previously that XO inhibition and radical scavenging could be useful properties for reduction of ROS-levels in tissue, we determined the chalcones’ effects to rescue neurons subjected to ROS-induced stress created by the addition of β-amyloid peptide. Best protection was provided by chalcones that combined good inhibitory potency with high radical scavenging ability in a single molecule, an observation that points to a potential therapeutic value of this compound class.

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