Prenylated flavonoids from Dalea genus as xanthine oxidase inhibitors: In vitro bioactivity evaluation and molecular docking studies

Prenylated flavanones are a family of compounds with an important biological potential. Previously, anti-tyrosinase activity, acetylcholinesterase inhibitory activity, and neuroprotective effects of several prenyl flavanones isolated from different American Dalea genus species were reported. The biological potency of these kinds of compounds, together with the particularity of their chemical structures, encouraged us to investigate them for in vitro and in silico anti-xanthine oxidase activity. So, five prenyl-flavanones obtained from different Dalea sp (Dalea elegans, Dalea boliviana, and Dalea pazensis) were studied and the relationships between the structure of these prenyl-flavanones and their inhibitory activity were evaluated. Molecular docking studies were performed in order to propose the binding mode of the most active natural compound. 2′,4′-dihydroxy-5′-(1‴,1‴-dimethylallyl)-8-prenylpinocembrin (1) was the most active in this series showing an IC50 of 0.26 ± 0.07 µM comparable with the reference inhibitor, allopurinol. The presence of 5,7,2′,4′-tetrahydroxy substitution, accompanied by a prenyl group at 8-position in the A-ring, and a 5′ (1‴,1‴-dimethylallyl) were important to present a xanthine oxidase inhibitory activity. This fact was confirmed with molecular docking studies showing relevant interactions of 1 with the residues of the catalytic site of xanthine oxidase, and a binding energy of −7.3297 kcal mol−1. These results contributed not only to understanding the binding mode but also to validating the in vitro results. The obtained findings lead us to propose these prenyl-flavanones as lead compounds for the design and development of novel xanthine oxidase inhibitors for the treatment of diseases in which this enzyme is involved

Xanthine oxidase inhibitory activity of natural and hemisynthetic flavonoids from Gardenia oudiepe (rubiaceae) in vitro and molecular docking studies

Xanthine oxidase (XO), an enzyme widely distributed among mammalian tissues, is associated with the oxidation of xanthine and hypoxanthine to form uric acid. Reactive oxygen species are also released during this process, leading to oxidative damages and to the pathology called gout. Available treatments mainly based on allopurinol cause serious side effects. Natural products such as flavonoids may represent an alternative. Thus, a series of polymethoxyflavones isolated and hemisynthesized from the bud exudates of Gardenia oudiepe has been evaluated for in vitro XO inhibitory activity. Compounds 1, 2 and 3 were more active than the reference inhibitor, Allopurinol (IC50 = 0.25 ± 0.004 μM) with IC50 values of (0.004 ± 0.001) μM, (0.05 ± 0.01) μM and (0.09 ± 0.003 μM), respectively. Structure-activity relationships were established. Additionally, a molecular docking study using MOE? tool was carried out to establish the binding mode of the most active flavones with the enzyme, showing important interactions with its catalytic residues.These promising results, suggest the use of these compounds as potential leads for the design and development of novel XO inhibitors.Fil: Santi, María Daniela. Universidad Nacional de Cordoba. Facultad de Ciencias Quimicas. Departamento de Farmacia. Catedra de Farmacognosia; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto Multidisciplinario de Biología Vegetal. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas Físicas y Naturales. Instituto Multidisciplinario de Biología Vegetal; ArgentinaFil: Paulino Zunini, M.. Universidad de la Republica. Facultad de Química; UruguayFil: Vera, B.. Universidad de la Republica. Facultad de Química; UruguayFil: Bouzidi, C.. Université Paris Descartes. Faculté des Sciences Pharmaceutiques et Biologiques; FranciaFil: Dumontet, V.. Laboratoire Plantes Médicinales de Nouméa; FranciaFil: Abin-Carriquiry, A.. Instituto de Investigaciones Biológicas Clemente Estable; UruguayFil: Grougnet, R.. Université Paris Descartes. Faculté Des Sciences Pharmaceutiques Et Biologiques; FranciaFil: Ortega, María Gabriela. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto Multidisciplinario de Biología Vegetal. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas Físicas y Naturales. Instituto Multidisciplinario de Biología Vegetal; Argentina. Universidad Nacional de Cordoba. Facultad de Ciencias Quimicas. Departamento de Farmacia. Catedra de Farmacognosia; Argentin