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

Abstract

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.

From Xanthine Oxidase Inhibition to In Vivo Hypouricemic Effect: An Integrated Overview of In Vitro and In Vivo Studies with Focus on Natural Molecules and Analogues

“…Cytotoxicity tests revealed that the most active of these chalcones is noncytotoxic. However, further structure modifications on the chalcone scaffold are needed to optimize the XO inhibitory activity [53]. Later, Xie et al described a synthetic series of hydroxychalcones ( Figure 15) with moderate XO inhibition, and in vitro IC 50 values of 47.3 and 56.8 μM were calculated for the most potent ones.…”

Toward an Understanding of Structural Insights of Xanthine and Aldehyde Oxidases: An Overview of their Inhibitors and Role in Various Diseases

“…SAR and molecular docking analyses revealed that 72 possessed a minimum of three hydroxyl groups that are required for XO inhibitory activity (Fig. ) . In 2017, Ali et al.…”

“…SAR and molecular docking analyses revealed that 72 possessed a minimum of three hydroxyl groups that are required for XO inhibitory activity (Fig. 16) 151. In 2017, Ali et al synthesized a new series of 2-(substituted benzylamine)-4-methylthiazole-5-carboxylic acid as structural analogs of febuxostat.…”

Design, synthesis, and biological evaluation of 5‐(4‐(pyridin‐4‐yl)‐1H‐1,2,3‐triazol‐1‐yl)benzonitrile derivatives as xanthine oxidase inhibitors

“…In general, topiroxostat analogues were not as abundant as febuxostat analogues, a typical representative is the pyridyl-1,2,4triazoles reported by Takahiro Sato et al [19] which possess excellent potency ( Figure 1). Furthermore, other XO inhibitors with various structural classes have also been recently published, including isocytosines, [5,[20][21][22] N-(1,3-diaryl-3oxo-propyl)amides, [23] N-acetyl pyrazolines, [24] hydroxylated chalcones, [25] 9-deazaguanines, [26] benzimidazoles, [27] flavonoids, [28,29] fraxamosides, [30] pyrano [3,2-d]pyrimidines, [31] 2-arylbenzo[b]furans [32] , and benzaldehydes. [33] We have focused on the structural modifications of fivemembered ring and the structure activity relationship (SAR) investigations of classical XO inhibitors.…”