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Since \u03b1-glucosidase inhibitors (AGIs) modulate intestinal metabolism, they may influence oxidative stress and glycolysis inhibition, potentially addressing intestinal dysfunction associated with T2DM. Herein, we report on a study of an ortho-carbonyl substituted hydroquinone series, whose members differ only in the number and position of methyl groups on a common scaffold, on radical-scavenging activities (ORAC assay) and correlate them with some parameters obtained by density functional theory (DFT) analysis. These compounds\u2019 effect on enzymatic activity, their molecular modeling on \u03b1-glucosidase, and their impact on the mitochondrial respiration and glycolysis of the intestinal Caco-2 cell line were evaluated. Three groups of compounds, according their effects on the Caco-2 cells metabolism, were characterized: group A (compounds 2, 3, 5, 8, 9, and 10) reduces the glycolysis, group B (compounds 1 and 6) reduces the basal mitochondrial oxygen consumption rate (OCR) and increases the extracellular acidification rate (ECAR), suggesting that it induces a metabolic remodeling toward glycolysis, and group C (compounds 4 and 7) increases the glycolysis lacking effect on OCR. Compounds 5 and 10 were more potent as \u03b1-glucosidase inhibitors (AGIs) than acarbose, a well-known AGI with clinical use. Moreover, compound 5 was an OCR\/ECAR inhibitor, and compound 10 was a dual agent, increasing the proton leak-driven OCR and inhibiting the maximal electron transport flux. Additionally, menadione-induced ROS production was prevented by compound 5 in Caco-2 cells. These results reveal that slight structural variations in a hydroquinone scaffold led to diverse antioxidant capability, \u03b1-glucosidase inhibition, and the regulation of mitochondrial bioenergetics in Caco-2 cells, which may be useful in the design of new drugs for T2DM and metabolic syndrome.<\/jats:p>","DOI":"10.3390\/ijms25158334","type":"journal-article","created":{"date-parts":[[2024,7,31]],"date-time":"2024-07-31T08:02:27Z","timestamp":1722412947000},"page":"8334","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Identification of Antioxidant Methyl Derivatives of Ortho-Carbonyl Hydroquinones That Reduce Caco-2 Cell Energetic Metabolism and Alpha-Glucosidase Activity"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-3694-5086","authenticated-orcid":false,"given":"Mat\u00edas","family":"Monroy-C\u00e1rdenas","sequence":"first","affiliation":[{"name":"Escuela de Qu\u00edmica, Facultad de Qu\u00edmica y de Farmacia, Pontificia Universidad Cat\u00f3lica de Chile, Av. Vicu\u00f1a Mackenna 4860, Santiago 7820436, Chile"},{"name":"MIBI\u2014Interdisciplinary Group on Mitochondrial Targeting and Bioenergetics, Universidad de Talca, P.O. Box 747, Talca 3460000, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-8861-806X","authenticated-orcid":false,"given":"Cristopher","family":"Almarza","sequence":"additional","affiliation":[{"name":"MIBI\u2014Interdisciplinary Group on Mitochondrial Targeting and Bioenergetics, Universidad de Talca, P.O. Box 747, Talca 3460000, Chile"},{"name":"Network for Snake Venom Research and Drug Discovery, Av. Independencia 1027, Santiago 7810000, Chile"},{"name":"Metabolic Plasticity and Bioenergetics Laboratory, Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Av. Independencia 1027, Santiago 7810000, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-6110-1573","authenticated-orcid":false,"given":"Paulina","family":"Valenzuela-Hormaz\u00e1bal","sequence":"additional","affiliation":[{"name":"Departamento de Farmacolog\u00eda, Facultad de Ciencias Biol\u00f3gicas, Universidad de Concepci\u00f3n, Concepci\u00f3n 4030000, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0002-1189","authenticated-orcid":false,"given":"David","family":"Ram\u00edrez","sequence":"additional","affiliation":[{"name":"Departamento de Farmacolog\u00eda, Facultad de Ciencias Biol\u00f3gicas, Universidad de Concepci\u00f3n, Concepci\u00f3n 4030000, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"F\u00e9lix A.","family":"Urra","sequence":"additional","affiliation":[{"name":"MIBI\u2014Interdisciplinary Group on Mitochondrial Targeting and Bioenergetics, Universidad de Talca, P.O. Box 747, Talca 3460000, Chile"},{"name":"Network for Snake Venom Research and Drug Discovery, Av. Independencia 1027, Santiago 7810000, Chile"},{"name":"Metabolic Plasticity and Bioenergetics Laboratory, Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Av. Independencia 1027, Santiago 7810000, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2959-3164","authenticated-orcid":false,"given":"Maximiliano","family":"Mart\u00ednez-Cifuentes","sequence":"additional","affiliation":[{"name":"Departamento de Qu\u00edmica Org\u00e1nica, Facultad de Ciencias Qu\u00edmicas, Universidad de Concepci\u00f3n, Edmundo Larenas 129, Concepci\u00f3n 4070371, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5082-9146","authenticated-orcid":false,"given":"Ramiro","family":"Araya-Maturana","sequence":"additional","affiliation":[{"name":"MIBI\u2014Interdisciplinary Group on Mitochondrial Targeting and Bioenergetics, Universidad de Talca, P.O. Box 747, Talca 3460000, Chile"},{"name":"Instituto de Qu\u00edmica de Recursos Naturales, Universidad de Talca, Talca 3460000, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,7,30]]},"reference":[{"key":"ref_1","unstructured":"Webber, S. (2013). IDF Diabetes Atlas, International Diabetes Federation. [10th ed.]."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Black, H.S. (2022). A Synopsis of the Associations of Oxidative Stress, ROS, and Antioxidants with Diabetes Mellitus. Antioxidants, 11.","DOI":"10.3390\/antiox11102003"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Wronka, M., Krzemi\u0144ska, J., M\u0142ynarska, E., Rysz, J., and Franczyk, B. (2022). The Influence of Lifestyle and Treatment on Oxidative Stress and Inflammation in Diabetes. Int. J. Mol. 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