Chromene flavanones from Dalea boliviana as xanthine oxidase inhibitors: in vitro biological evaluation and molecular docking studies
BackgroundPrenylated flavanones represent a structurally diverse class of natural compounds with significant biological potential. Among them, chromene flavanones (CFs) constitute a rare and specialized subgroup with promising therapeutic applications. These molecules have gained attention due to th...
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Frontiers Media S.A.
2025-04-01
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| author | Einy Nallybe Bedoya Aguirre Einy Nallybe Bedoya Aguirre María Daniela Santi Melisa Fabiana Negro Melisa Fabiana Negro Javier Echeverría Margot Paulino Zunini Mariana Andrea Peralta Mariana Andrea Peralta María Gabriela Ortega María Gabriela Ortega |
| author_facet | Einy Nallybe Bedoya Aguirre Einy Nallybe Bedoya Aguirre María Daniela Santi Melisa Fabiana Negro Melisa Fabiana Negro Javier Echeverría Margot Paulino Zunini Mariana Andrea Peralta Mariana Andrea Peralta María Gabriela Ortega María Gabriela Ortega |
| author_sort | Einy Nallybe Bedoya Aguirre |
| collection | DOAJ |
| description | BackgroundPrenylated flavanones represent a structurally diverse class of natural compounds with significant biological potential. Among them, chromene flavanones (CFs) constitute a rare and specialized subgroup with promising therapeutic applications. These molecules have gained attention due to their potential to inhibit xanthine oxidase (XO), a key enzyme involved in oxidative stress-related disorders such as gout and hyperuricemia. Their distinctive structural features, combined with notable bioactivity, make them compelling candidates for further pharmacological exploration. Given their potential relevance, this study focuses on the in vitro and in silico evaluation of three CFs isolated from Dalea boliviana Britton [Fabacea], assessing their capacity to inhibit XO and elucidating key structure–activity relationships (SARs) that contribute to their biological effectiveness.PurposeThis study aims to investigate the in vitro and in silico interactions of the chromene flavanones, namely, (2S) 5,2′-dihydroxy-6″,6″-dimethylchromeno-(7,8:2″,3″)-flavanone (1), (2S) 5,2′-dihydroxy-6″,6″-dimethylchromeno-(7,8:2″,3″)-3′-prenylflavanone (2), and obovatin (3), obtained from D. boliviana, with XO, in order to explore their potential as XO inhibitors and their potential therapeutic applications for hyperuricemic diseases.Material and MethodsXO inhibition by the three chromene flavanones was measured spectroscopically. The relationships between their structures and inhibitory activities were evaluated. Moreover, molecular docking studies were performed to propose the binding modes of the most active natural compounds.Results and discussionCompounds 1 and 2 exhibited potent inhibition, with IC50 values in the nanomolar range (0.5 ± 0.01 nM and 1.7 ± 0.46 nM, respectively), demonstrating significantly higher activity than allopurinol (AL), the reference inhibitor (IC50 = 247 ± 4 nM). In contrast, compound 3 displayed only weak inhibition. SAR analysis revealed that the presence of a chromene moiety in the A-ring, combined with hydroxyl and prenyl groups in the B-ring, played a crucial role in enhancing inhibitory activity. Molecular docking studies confirmed the strong binding affinities of compounds 1 and 2 within the active site of XO (PDB ID: 3NVY), with binding energies of −6.1687 kcal/mol and −6.7820 kcal/mol, respectively. Key stabilizing interactions involved π–π interactions with Phe914 and hydrogen bonding with residues such as Leu873 and Leu1014. These findings highlight the structural features essential for potent XO inhibition and suggest that chromene flavanones represent a valuable scaffold for the development of novel inhibitors. Further molecular dynamics simulations could provide deeper insights into their stability and interaction dynamics, aiding in the rational design of more effective XO inhibitors.ConclusionOur findings lead us to propose these chromene flavanones as lead compounds for the design and development of novel XO inhibitors for treating diseases in which exacerbated activity of this enzyme is involved. |
| format | Article |
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| issn | 1663-9812 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Pharmacology |
| spelling | doaj-art-6504ac81acee4be1bde7e596265f4d612025-08-20T03:14:13ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122025-04-011610.3389/fphar.2025.15763901576390Chromene flavanones from Dalea boliviana as xanthine oxidase inhibitors: in vitro biological evaluation and molecular docking studiesEiny Nallybe Bedoya Aguirre0Einy Nallybe Bedoya Aguirre1María Daniela Santi2Melisa Fabiana Negro3Melisa Fabiana Negro4Javier Echeverría5Margot Paulino Zunini6Mariana Andrea Peralta7Mariana Andrea Peralta8María Gabriela Ortega9María Gabriela Ortega10Unidad de Investigación y Desarrollo en Tecnología Farmacéutica (UNITEFA-CONICET), Ciudad Universitaria, Córdoba, ArgentinaFarmacognosia, Departamento de Ciencias Farmacéuticas, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Ciudad Universitaria, Córdoba, ArgentinaMax Planck Institute for Multidisciplinary Sciences, NMR Signal Enhancement group, Goettingen, GermanyUnidad de Investigación y Desarrollo en Tecnología Farmacéutica (UNITEFA-CONICET), Ciudad Universitaria, Córdoba, ArgentinaFarmacognosia, Departamento de Ciencias Farmacéuticas, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Ciudad Universitaria, Córdoba, ArgentinaDepartamento de Ciencias del Ambiente, Facultad de Química y Biología, Universidad de Santiago de Chile, Santiago, ChileÁrea Bioinformática, Departamento de Experimentación y Teoría de la Materia (Detema), Facultad de Química, Universidad de la República, Montevideo, UruguayUnidad de Investigación y Desarrollo en Tecnología Farmacéutica (UNITEFA-CONICET), Ciudad Universitaria, Córdoba, ArgentinaFarmacognosia, Departamento de Ciencias Farmacéuticas, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Ciudad Universitaria, Córdoba, ArgentinaUnidad de Investigación y Desarrollo en Tecnología Farmacéutica (UNITEFA-CONICET), Ciudad Universitaria, Córdoba, ArgentinaFarmacognosia, Departamento de Ciencias Farmacéuticas, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Ciudad Universitaria, Córdoba, ArgentinaBackgroundPrenylated flavanones represent a structurally diverse class of natural compounds with significant biological potential. Among them, chromene flavanones (CFs) constitute a rare and specialized subgroup with promising therapeutic applications. These molecules have gained attention due to their potential to inhibit xanthine oxidase (XO), a key enzyme involved in oxidative stress-related disorders such as gout and hyperuricemia. Their distinctive structural features, combined with notable bioactivity, make them compelling candidates for further pharmacological exploration. Given their potential relevance, this study focuses on the in vitro and in silico evaluation of three CFs isolated from Dalea boliviana Britton [Fabacea], assessing their capacity to inhibit XO and elucidating key structure–activity relationships (SARs) that contribute to their biological effectiveness.PurposeThis study aims to investigate the in vitro and in silico interactions of the chromene flavanones, namely, (2S) 5,2′-dihydroxy-6″,6″-dimethylchromeno-(7,8:2″,3″)-flavanone (1), (2S) 5,2′-dihydroxy-6″,6″-dimethylchromeno-(7,8:2″,3″)-3′-prenylflavanone (2), and obovatin (3), obtained from D. boliviana, with XO, in order to explore their potential as XO inhibitors and their potential therapeutic applications for hyperuricemic diseases.Material and MethodsXO inhibition by the three chromene flavanones was measured spectroscopically. The relationships between their structures and inhibitory activities were evaluated. Moreover, molecular docking studies were performed to propose the binding modes of the most active natural compounds.Results and discussionCompounds 1 and 2 exhibited potent inhibition, with IC50 values in the nanomolar range (0.5 ± 0.01 nM and 1.7 ± 0.46 nM, respectively), demonstrating significantly higher activity than allopurinol (AL), the reference inhibitor (IC50 = 247 ± 4 nM). In contrast, compound 3 displayed only weak inhibition. SAR analysis revealed that the presence of a chromene moiety in the A-ring, combined with hydroxyl and prenyl groups in the B-ring, played a crucial role in enhancing inhibitory activity. Molecular docking studies confirmed the strong binding affinities of compounds 1 and 2 within the active site of XO (PDB ID: 3NVY), with binding energies of −6.1687 kcal/mol and −6.7820 kcal/mol, respectively. Key stabilizing interactions involved π–π interactions with Phe914 and hydrogen bonding with residues such as Leu873 and Leu1014. These findings highlight the structural features essential for potent XO inhibition and suggest that chromene flavanones represent a valuable scaffold for the development of novel inhibitors. Further molecular dynamics simulations could provide deeper insights into their stability and interaction dynamics, aiding in the rational design of more effective XO inhibitors.ConclusionOur findings lead us to propose these chromene flavanones as lead compounds for the design and development of novel XO inhibitors for treating diseases in which exacerbated activity of this enzyme is involved.https://www.frontiersin.org/articles/10.3389/fphar.2025.1576390/fullDalea bolivianachromene flavanonesxanthine oxidase inhibitionmolecular dockinggout, hyperuricemia |
| spellingShingle | Einy Nallybe Bedoya Aguirre Einy Nallybe Bedoya Aguirre María Daniela Santi Melisa Fabiana Negro Melisa Fabiana Negro Javier Echeverría Margot Paulino Zunini Mariana Andrea Peralta Mariana Andrea Peralta María Gabriela Ortega María Gabriela Ortega Chromene flavanones from Dalea boliviana as xanthine oxidase inhibitors: in vitro biological evaluation and molecular docking studies Frontiers in Pharmacology Dalea boliviana chromene flavanones xanthine oxidase inhibition molecular docking gout, hyperuricemia |
| title | Chromene flavanones from Dalea boliviana as xanthine oxidase inhibitors: in vitro biological evaluation and molecular docking studies |
| title_full | Chromene flavanones from Dalea boliviana as xanthine oxidase inhibitors: in vitro biological evaluation and molecular docking studies |
| title_fullStr | Chromene flavanones from Dalea boliviana as xanthine oxidase inhibitors: in vitro biological evaluation and molecular docking studies |
| title_full_unstemmed | Chromene flavanones from Dalea boliviana as xanthine oxidase inhibitors: in vitro biological evaluation and molecular docking studies |
| title_short | Chromene flavanones from Dalea boliviana as xanthine oxidase inhibitors: in vitro biological evaluation and molecular docking studies |
| title_sort | chromene flavanones from dalea boliviana as xanthine oxidase inhibitors in vitro biological evaluation and molecular docking studies |
| topic | Dalea boliviana chromene flavanones xanthine oxidase inhibition molecular docking gout, hyperuricemia |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2025.1576390/full |
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