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

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

  • ChemMedChem. 2023 Oct 6:e202300400. doi: 10.1002/cmdc.202300400.
Antonella Fais 1,  Francesca Pintus 1,  Benedetta Era 1,  Sonia Floris 1,  Amit Kumar 2,  Debapriyo Sarmadhikari 3,  Valeria Sogos 4,  Eugenio Uriarte 5 6,  Shailendra Asthana 3,  Maria João Matos 5
Affiliations

Affiliations

  • 1 Department of Life and Environmental Sciences, University of Cagliari, S.P. 8 km 0.700, 09042, Cagliari, Italy.
  • 2 Department of Electrical and Electronic Engineering, University of Cagliari, Via Marengo 2, 09123, Cagliari, Italy.
  • 3 Translational Health Science and Technology Institute, NCR Biotech Science Cluster, Faridabad, 121001, India.
  • 4 Department of Biomedical Sciences, University of Cagliari, S.P. 8 km 0.700, 09042, Monserrato, Italy.
  • 5 Departamento de Química Orgánica, Facultade de Farmacia, Universidade Santiago de Compostela, 15782, Santiago de Compostela, Spain.
  • 6 Instituto de Ciencias Químicas Aplicadas, Universidad Autónoma de Chile, 7500912, Santiago, Chile.
PMID: 37801332 DOI: 10.1002/cmdc.202300400
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.

Keywords

Hydroxy-3-phenylcoumarins; Hydroxy-3-thienylcoumarins; Molecular docking; Xanthine oxidase.

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