{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T21:23:44Z","timestamp":1777497824540,"version":"3.51.4"},"reference-count":31,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2022,10,15]],"date-time":"2022-10-15T00:00:00Z","timestamp":1665792000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ministerio de Ciencia e Innovaci\u00f3n","award":["PID2020-116076RJ-I00\/AEI\/10.13039\/501100011033"],"award-info":[{"award-number":["PID2020-116076RJ-I00\/AEI\/10.13039\/501100011033"]}]},{"name":"University of Cagliari","award":["PID2020-116076RJ-I00\/AEI\/10.13039\/501100011033"],"award-info":[{"award-number":["PID2020-116076RJ-I00\/AEI\/10.13039\/501100011033"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Skin aging is a progressive biological process of the human body, and it is not only time-dependent. Differently substituted 3-phenylcoumarins proved to efficiently inhibit tyrosinase. In the current work, new substitution patterns have been explored, and the biological studies were extended to other important enzymes involved in the processes of skin aging, as elastase, collagenase and hyaluronidase. From the studied series, five compounds presented inhibitory activity against tyrosinase, one compound against elastase, eight compounds against collagenase and two compounds against hyaluronidase, being five compounds dual inhibitors. The 3-(4\u2032-Bromophenyl)-5,7-dihydroxycoumarin (1) and 3-(3\u2032-bromophenyl)-5,7-dihydroxycoumarin (2) presented the best profiles against tyrosinase (IC50 = 1.05 \u00b5M and 7.03 \u00b5M) and collagenase (IC50 = 123.4 \u00b5M and 110.4 \u00b5M); the 3-(4\u2032-bromophenyl)-6,7-dihydroxycoumarin (4) presented a good inhibition against tyrosinase and hyaluronidase; the 3-(3\u2032-bromophenyl)-6,7-dihydroxycoumarin (5) showed an effective tyrosinase and elastase inhibition; and 6,7-dihydroxy-3-(3\u2032-hydroxyphenyl)coumarin (11) presented a dual profile inhibition against collagenase and hyaluronidase. Furthermore, considering the overall activities tested, compounds 1 and 2 proved to be the most promising anti-aging compounds. These compounds also showed to have a photo-protective effect, without being cytotoxic to human skin keratinocyte cells. To predict the binding site with the target enzymes, computational studies were also carried out.<\/jats:p>","DOI":"10.3390\/molecules27206914","type":"journal-article","created":{"date-parts":[[2022,10,17]],"date-time":"2022-10-17T03:43:58Z","timestamp":1665978238000},"page":"6914","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["Hydroxy-3-Phenylcoumarins as Multitarget Compounds for Skin Aging Diseases: Synthesis, Molecular Docking and Tyrosinase, Elastase, Collagenase and Hyaluronidase Inhibition, and Sun Protection Factor"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2350-7966","authenticated-orcid":false,"given":"Francesca","family":"Pintus","sequence":"first","affiliation":[{"name":"Department of Life and Environmental Sciences, University of Cagliari, 09042 Monserrato, Italy"}]},{"given":"Sonia","family":"Floris","sequence":"additional","affiliation":[{"name":"Department of Life and Environmental Sciences, University of Cagliari, 09042 Monserrato, Italy"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3009-4226","authenticated-orcid":false,"given":"Antonella","family":"Fais","sequence":"additional","affiliation":[{"name":"Department of Life and Environmental Sciences, University of Cagliari, 09042 Monserrato, Italy"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4154-9740","authenticated-orcid":false,"given":"Benedetta","family":"Era","sequence":"additional","affiliation":[{"name":"Department of Life and Environmental Sciences, University of Cagliari, 09042 Monserrato, Italy"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2547-0071","authenticated-orcid":false,"given":"Amit","family":"Kumar","sequence":"additional","affiliation":[{"name":"Department of Electrical and Electronic Engineering, University of Cagliari, 09123 Cagliari, Italy"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0615-4177","authenticated-orcid":false,"given":"Gianluca","family":"Gatto","sequence":"additional","affiliation":[{"name":"Department of Electrical and Electronic Engineering, University of Cagliari, 09123 Cagliari, Italy"}]},{"given":"Eugenio","family":"Uriarte","sequence":"additional","affiliation":[{"name":"Departamento de Qu\u00edmica Org\u00e1nica, Facultade de Farmacia, Universidade Santiago de Compostela, 15782 Santiago de Compostela, Spain"},{"name":"Instituto de Ciencias Qu\u00edmicas Aplicadas, Universidad Aut\u00f3noma de Chile, Santiago 7500912, Chile"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3470-8299","authenticated-orcid":false,"given":"Maria Jo\u00e3o","family":"Matos","sequence":"additional","affiliation":[{"name":"Departamento de Qu\u00edmica Org\u00e1nica, Facultade de Farmacia, Universidade Santiago de Compostela, 15782 Santiago de Compostela, Spain"}]}],"member":"1968","published-online":{"date-parts":[[2022,10,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1213","DOI":"10.1016\/j.jid.2016.11.045","article-title":"Human Skin Is the Largest Epithelial Surface for Interaction with Microbes","volume":"137","author":"Gallo","year":"2017","journal-title":"J. Investig. Dermatol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1016\/j.molmed.2021.12.003","article-title":"Skin senescence: Mechanisms and impact on whole-body aging","volume":"28","author":"Franco","year":"2022","journal-title":"Trends Mol. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1515","DOI":"10.2174\/0929867322666150227151809","article-title":"Potential role of natural compounds against skin aging","volume":"22","author":"Tundis","year":"2015","journal-title":"Curr. Med. Chem."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"115873","DOI":"10.1016\/j.bmc.2020.115873","article-title":"Xanthones for melanogenesis inhibition: Molecular docking and QSAR studies to understand their anti-tyrosinase activity","volume":"29","author":"Rosa","year":"2021","journal-title":"Biorg. Med. Chem."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1111\/dth.14095","article-title":"The top 10 cosmeceuticals for facial hyperpigmentation","volume":"33","author":"Searle","year":"2020","journal-title":"Dermatol. Ther."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1016\/j.ijbiomac.2019.08.027","article-title":"Unravelling property of polysaccharides from Sargassum sp. as an anti-wrinkle and skin whitening property","volume":"140","author":"Jesumani","year":"2019","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"7753","DOI":"10.3390\/ijms16047753","article-title":"Biological mechanisms underlying the ultraviolet radiation-induced formation of skin wrinkling and sagging I: Reduced skin elasticity, highly associated with enhanced dermal elastase activity, triggers wrinkling and sagging","volume":"16","author":"Imokawa","year":"2015","journal-title":"Int. J. Mol. Sci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1080\/14756366.2020.1862099","article-title":"Screening the dermatological potential of plectranthus species components: Antioxidant and inhibitory capacities over elastase, collagenase and tyrosinase","volume":"36","author":"Andrade","year":"2021","journal-title":"J. Enzyme Inhib. Med. Chem."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"415102","DOI":"10.1088\/1361-6528\/ac027b","article-title":"Antioxidant and anti-aging carbon quantum dots using tannic acid","volume":"32","author":"Son","year":"2021","journal-title":"Nanotechnology"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1687","DOI":"10.1016\/j.bmc.2017.01.037","article-title":"New insights into highly potent tyrosinase inhibitors based on 3-heteroarylcoumarins: Anti-melanogenesis and antioxidant activities, and computational molecular modeling studies","volume":"25","author":"Pintus","year":"2017","journal-title":"Bioorgan. Med. Chem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"94227","DOI":"10.1039\/C5RA14465E","article-title":"Design and discovery of tyrosinase inhibitors based on a coumarin scaffold","volume":"5","author":"Matos","year":"2015","journal-title":"RSC Adv."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"742","DOI":"10.1111\/j.2042-7158.2012.01467.x","article-title":"Tyrosine-like condensed derivatives as tyrosinase inhibitors","volume":"64","author":"Matos","year":"2012","journal-title":"J. Pharm. Pharmacol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"3342","DOI":"10.1016\/j.bmcl.2011.04.012","article-title":"New halogenated phenylcoumarins as tyrosinase inhibitors","volume":"21","author":"Matos","year":"2011","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2514","DOI":"10.3390\/molecules14072514","article-title":"Tyrosinase inhibitor activity of coumarin-resveratrol hybrids","volume":"14","author":"Fais","year":"2009","journal-title":"Molecules"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"W530","DOI":"10.1093\/nar\/gkab294","article-title":"PLIP 2021: Expanding the scope of the protein-ligand interaction profiler to DNA and RNA","volume":"49","author":"Adasme","year":"2021","journal-title":"Nucleic Acids Res."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Mechqoq, H., Hourfane, S., El Yaagoubi, M., Hamdaoui, A.E., da Almeida, J.R.G.S., Rocha, J.M., and Aouad, N.E. (2022). Molecular Docking, Tyrosinase, Collagenase, and Elastase Inhibition Activities of Argan By-Products. Cosmetics, 9.","DOI":"10.3390\/cosmetics9010024"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1255","DOI":"10.1016\/j.csbj.2019.07.017","article-title":"In vitro and in silico insights into tyrosinase inhibitors with (E)-benzylidene-1-indanone derivatives","volume":"17","author":"Jung","year":"2019","journal-title":"Comput. Struct. Biotechnol. J."},{"key":"ref_18","first-page":"20200625","article-title":"Cancer metastasis inhibitor containing phenyl coumarin derivative, and its combinational use","volume":"130120","author":"Ashihara","year":"2020","journal-title":"PCT Int. Appl."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"520","DOI":"10.1111\/cbdd.13669","article-title":"Inhibition of human CYP1 enzymes by a classical inhibitor \u03b1-naphthoflavone and a novel inhibitor N-(3, 5-dichlorophenyl)cyclopropanecarboxamide: An in vitro and in silico study","volume":"95","author":"Juvonen","year":"2020","journal-title":"Chem. Biol. Drug Des."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"371","DOI":"10.4155\/fmc.14.9","article-title":"Synthesis, pharmacological study and docking calculations of new benzo[f]coumarin derivatives as dual inhibitors of enzymatic systems involved in neurodegenerative diseases","volume":"6","author":"Matos","year":"2014","journal-title":"Future Med. Chem."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Chompoo, J., Upadhyay, A., Fukuta, M., and Tawata, S. (2012). Effect of Alpinia zerumbet components on antioxidant and skin diseases-related enzymes. BMC Complement. Altern. Med., 12.","DOI":"10.1186\/1472-6882-12-106"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Era, B., Floris, S., Sogos, V., Porcedda, C., Piras, A., Medda, R., Fais, A., and Pintus, F. (2021). Anti-aging potential of extracts from Washingtonia filifera seeds. Plants, 10.","DOI":"10.3390\/plants10010151"},{"key":"ref_23","first-page":"121","article-title":"Determina\u00e7\u00e3o Do Fator De Prote\u00e7\u00e3o Solar Por Espectrofotometria","volume":"61","author":"Mansur","year":"1986","journal-title":"An. Bras. Dermatol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1111\/j.1751-1097.1979.tb07090.x","article-title":"Comparison of in Vivo and in Vitro Testing of Sunscreening Formulas","volume":"29","author":"Sayre","year":"1979","journal-title":"Photochem. Photobiol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1038\/nsb0294-106","article-title":"Structure of the catalytic domain of human fibroblast collagenase complexed with an inhibitor","volume":"1","author":"Borkakot","year":"1994","journal-title":"Nat. Struct. Biol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"5477","DOI":"10.1021\/bi200395t","article-title":"Crystal structure of agaricus bisporus mushroom tyrosinase: Identity of the tetramer subunits and interaction with tropolone","volume":"50","author":"Ismaya","year":"2011","journal-title":"Biochemistry"},{"key":"ref_27","unstructured":"(2022, September 01). Available online: https:\/\/chemaxon.com\/."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1186\/1758-2946-3-33","article-title":"Open Babel: An Open chemical toolbox","volume":"3","author":"Banck","year":"2011","journal-title":"J. Cheminform."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Kumar, A., Baccoli, R., Fais, A., Cincotti, A., Pilia, L., and Gatto, G. (2020). Substitution effects on the optoelectronic properties of coumarin derivatives. Appl. Sci., 10.","DOI":"10.3390\/app10010144"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"W438","DOI":"10.1093\/nar\/gky439","article-title":"COACH-D: Improved protein-ligand binding sites prediction with refined ligand-binding poses through molecular docking","volume":"46","author":"Wu","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1002\/jcc.21334","article-title":"AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading","volume":"31","author":"Trott","year":"2010","journal-title":"J. Comput. Chem."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/27\/20\/6914\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:54:36Z","timestamp":1760144076000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/27\/20\/6914"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,10,15]]},"references-count":31,"journal-issue":{"issue":"20","published-online":{"date-parts":[[2022,10]]}},"alternative-id":["molecules27206914"],"URL":"https:\/\/doi.org\/10.3390\/molecules27206914","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,10,15]]}}}