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Design of 3-Phenylcoumarins and 3-Thienylcoumarins as Potent Xanthine Oxidase Inhibitors: Synthesis, Biological Evaluation, and Docking Studies.

Published version
Peer-reviewed

Repository DOI


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Authors

Fais, Antonella 
Pintus, Francesca 
Era, Benedetta 
Kumar, Amit 

Abstract

Coumarin scaffold has proven to be promising in the development of bioactive agents, such as xanthine oxidase (XO) inhibitors. Novel hydroxylated 3-arylcoumarins were designed, synthesized, and evaluated for their XO inhibition and antioxidant properties. 3-(3'-Bromophenyl)-5,7-dihydroxycoumarin (compound 11) proved to be the most potent XO inhibitor, with an IC50 of 91 nM, being 162 times better than allopurinol, one of the reference controls. Kinetic analysis of compound 11 and compound 5 [3-(4'-bromothien-2'-yl)-5,7-dihydroxycoumarin], the second-best compound within the series (IC50 of 280 nM), has been performed, and both compounds showed a mixed-type inhibition. Both compounds present good antioxidant activity (ability to scavenge ABTS radical) and are able to reduce reactive oxygen species (ROS) levels in H2 O2 -treated cells. In addition, they proved to be non-cytotoxic in a Caco-2 cells viability assay. Molecular docking studies have been carried out to correlate the compounds' theoretical and experimental binding affinity to the XO binding pocket.

Description

Publication status: Published

Keywords

Hydroxy-3-phenylcoumarins, Hydroxy-3-thienylcoumarins, Molecular docking, Xanthine oxidase, Humans, Structure-Activity Relationship, Xanthine Oxidase, Molecular Docking Simulation, Caco-2 Cells, Kinetics, Enzyme Inhibitors, Antioxidants

Journal Title

ChemMedChem

Conference Name

Journal ISSN

1860-7179
1860-7187

Volume Title

Publisher

Wiley
Sponsorship
Ministerio de Ciencia e Innovación (PID2020-116076RJ-I00/AEI/10.13039/501100011033)