{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T02:47:18Z","timestamp":1790390838425,"version":"4.1.0"},"reference-count":34,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2023,9,29]],"date-time":"2023-09-29T00:00:00Z","timestamp":1695945600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Research Foundation of Korea","award":["NRF-2020R1A2C1004198"],"award-info":[{"award-number":["NRF-2020R1A2C1004198"]}]},{"name":"National Research Foundation of Korea","award":["NRF-2021R1I1A1A01052284"],"award-info":[{"award-number":["NRF-2021R1I1A1A01052284"]}]},{"name":"National Research Foundation of Korea","award":["NRF-2020R1A2C1004198"],"award-info":[{"award-number":["NRF-2020R1A2C1004198"]}]},{"name":"National Research Foundation of Korea","award":["NRF-2021R1I1A1A01052284"],"award-info":[{"award-number":["NRF-2021R1I1A1A01052284"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>Ten 2-mercaptobenzimidazole (2-MBI) analogs were synthesized as potential tyrosinase inhibitors because mercapto-containing compounds can bind to copper ions at the active site of tyrosinase to inhibit enzyme activity. Nine 2-MBI analogs showed sub-micromolar IC50 values for mushroom tyrosinase monophenolase activity; analog 4 was 280-fold more potent than kojic acid, and in diphenolase activity, 6 was 970-fold more potent than kojic acid. The inhibition mode of the 2-MBI analogs was investigated using kinetic studies supported by docking simulations. Benzimidazoles without the 2-mercapto substituent of the 2-MBI analogs lost their tyrosinase inhibitory activity, implying that the 2-mercapto substituent plays an important role in tyrosinase inhibition. The 2-MBI analogs exerted potent antioxidant effects against 2,2\u2032-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid (ABTS), 2,2-diphenyl-1-picrylhydrazyl (DPPH), and reactive oxygen species (ROS). The results obtained from apple slices and human embryonic kidney cells (HEK-293) suggest that most 2-MBI analogs are sufficiently safe candidates to delay the browning of apple slices effectively. Thus, these results support the potential use of 2-MBI analogs as anti-browning agents in foods such as mushrooms, vegetables, and fruits.<\/jats:p>","DOI":"10.3390\/antiox12101814","type":"journal-article","created":{"date-parts":[[2023,10,1]],"date-time":"2023-10-01T16:58:09Z","timestamp":1696179489000},"page":"1814","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Anti-Browning Effect of 2-Mercaptobenzo[d]imidazole Analogs with Antioxidant Activity on Freshly-Cut Apple Slices and Their Highly Potent Tyrosinase Inhibitory Activity"],"prefix":"10.3390","volume":"12","author":[{"given":"Jieun","family":"Lee","sequence":"first","affiliation":[{"name":"Department of Manufacturing Pharmacy, College of Pharmacy and Research Institute for Drug Development, Pusan National University, Busan 46241, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hye Soo","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Manufacturing Pharmacy, College of Pharmacy and Research Institute for Drug Development, Pusan National University, Busan 46241, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7212-5572","authenticated-orcid":false,"given":"Hee Jin","family":"Jung","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, College of Pharmacy and Research Institute for Drug Development, Pusan National University, Busan 46241, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu Jung","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Manufacturing Pharmacy, College of Pharmacy and Research Institute for Drug Development, Pusan National University, Busan 46241, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min Kyung","family":"Kang","sequence":"additional","affiliation":[{"name":"Department of Manufacturing Pharmacy, College of Pharmacy and Research Institute for Drug Development, Pusan National University, Busan 46241, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hye Jin","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Manufacturing Pharmacy, College of Pharmacy and Research Institute for Drug Development, Pusan National University, Busan 46241, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dahye","family":"Yoon","sequence":"additional","affiliation":[{"name":"Department of Manufacturing Pharmacy, College of Pharmacy and Research Institute for Drug Development, Pusan National University, Busan 46241, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sultan","family":"Ullah","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, Jupiter, FL 33458, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongwan","family":"Kang","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu 41061, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yujin","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu 41061, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pusoon","family":"Chun","sequence":"additional","affiliation":[{"name":"College of Pharmacy and Inje Institute of Pharmaceutical Sciences and Research, Inje University, Gimhae 50834, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3215-8828","authenticated-orcid":false,"given":"Hae Young","family":"Chung","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, College of Pharmacy and Research Institute for Drug Development, Pusan National University, Busan 46241, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1119-7112","authenticated-orcid":false,"given":"Hyung Ryong","family":"Moon","sequence":"additional","affiliation":[{"name":"Department of Manufacturing Pharmacy, College of Pharmacy and Research Institute for Drug Development, Pusan National University, Busan 46241, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,9,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"520","DOI":"10.1111\/pcmr.12393","article-title":"Melanins and melanogenesis: From pigment cells to human health and technological applications","volume":"28","author":"Wakamatsu","year":"2015","journal-title":"Pigment Cell Melanoma Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"4620","DOI":"10.1016\/j.bmc.2016.07.068","article-title":"2-(4-Fluorophenyl)-quinazolin-4(3H)-one as a novel tyrosinase inhibitor: Synthesis, inhibitory activity, and mechanism","volume":"24","author":"Wang","year":"2016","journal-title":"Bioorg. Med. Chem."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1016\/j.clindermatol.2019.07.013","article-title":"The physiology of melanin deposition in health and disease","volume":"37","author":"Lambert","year":"2019","journal-title":"Clin. Dermatol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"S43","DOI":"10.1007\/s00403-007-0807-0","article-title":"Melanin mediated apoptosis of epidermal cells damaged by ultraviolet radiation: Factors influencing the incidence of skin cancer","volume":"300","author":"Yamaguchi","year":"2008","journal-title":"Arch. Dermatol. Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"572","DOI":"10.1111\/j.1600-0749.2006.00345.x","article-title":"The physical and chemical properties of eumelanin","volume":"19","author":"Meredith","year":"2006","journal-title":"Pigment Cell Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1111\/1744-7917.12038","article-title":"Tyrosine metabolic enzymes from insects and mammals: A comparative perspective","volume":"21","author":"Vavricka","year":"2014","journal-title":"Insect Sci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1016\/j.pneurobio.2015.09.012","article-title":"Interactions of iron, dopamine and neuromelanin pathways in brain aging and Parkinson\u2019s disease","volume":"155","author":"Zucca","year":"2017","journal-title":"Prog. Neurobiol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1046\/j.1462-5814.2003.00268.x","article-title":"The contribution of melanin to microbial pathogenesis","volume":"5","author":"Nosanchuk","year":"2003","journal-title":"Cell Microbiol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2902","DOI":"10.1096\/fasebj.5.14.1752358","article-title":"Enzymatic control of pigmentation in mammals","volume":"5","author":"Hearing","year":"1991","journal-title":"FASEB J."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Vittorio, S., Dank, C., and Ielo, L. (2023). Heterocyclic Compounds as Synthetic Tyrosinase Inhibitors: Recent Advances. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24109097"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1021\/jf950394r","article-title":"Food Browning and Its Prevention:\u2009 An Overview","volume":"44","author":"Friedman","year":"1996","journal-title":"J. Agric. Food Chem."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Lee, H.K., Ha, J.W., Hwang, Y.J., and Boo, Y.C. (2021). Identification of L-Cysteinamide as a Potent Inhibitor of Tyrosinase-Mediated Dopachrome Formation and Eumelanin Synthesis. Antioxidants, 10.","DOI":"10.3390\/antiox10081202"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"155","DOI":"10.2340\/0001555564155157","article-title":"Inactivation of human tyrosinase by cysteine. Protection by dopa and tyrosine","volume":"64","author":"Jergil","year":"1984","journal-title":"Acta Derm.-Venereol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1021\/acschemneuro.1c00560","article-title":"Discovery of Resorcinol-Based Polycyclic Structures as Tyrosinase Inhibitors for Treatment of Parkinson\u2019s Disease","volume":"13","author":"Li","year":"2022","journal-title":"ACS Chem. Neurosci."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"414","DOI":"10.1016\/j.bioorg.2018.10.069","article-title":"1,2,3-Triazole-based kojic acid analogs as potent tyrosinase inhibitors: Design, synthesis and biological evaluation","volume":"82","author":"Ashooriha","year":"2019","journal-title":"Bioorg. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Lu, Y., Tonissen, K.F., and Di Trapani, G. (2021). Modulating skin colour: Role of the thioredoxin and glutathione systems in regulating melanogenesis. Biosci. Rep., 41.","DOI":"10.1042\/BSR20210427"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Ryu, I.Y., Choi, I., Jung, H.J., Ullah, S., Choi, H., Al-Amin, M., Chun, P., and Moon, H.R. (2021). In vitro anti-melanogenic effects of chimeric compounds, 2-(substituted benzylidene)-1,3-indanedione derivatives with a \u03b2-phenyl-\u03b1, \u03b2 -unsaturated dicarbonyl scaffold. Bioorg. Chem., 109.","DOI":"10.1016\/j.bioorg.2021.104688"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Jung, H.J., Choi, D.C., Noh, S.G., Choi, H., Choi, I., Ryu, I.Y., Chung, H.Y., and Moon, H.R. (2021). New Benzimidazothiazolone Derivatives as Tyrosinase Inhibitors with Potential Anti-Melanogenesis and Reactive Oxygen Species Scavenging Activities. Antioxidants, 10.","DOI":"10.3390\/antiox10071078"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Jeong, Y., Hong, S., Jung, H.J., Ullah, S., Hwang, Y., Choi, H., Ko, J., Lee, J., Chun, P., and Chung, H.Y. (2022). Identification of a Novel Class of Anti-Melanogenic Compounds, (Z)-5-(Substituted benzylidene)-3-phenyl-2-thioxothiazolidin-4-one Derivatives, and Their Reactive Oxygen Species Scavenging Activities. Antioxidants, 11.","DOI":"10.3390\/antiox11050948"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"899","DOI":"10.1016\/j.csbj.2022.02.007","article-title":"Identification of (Z)-2-benzylidene-dihydroimidazothiazolone derivatives as tyrosinase inhibitors: Anti-melanogenic effects and in silico studies","volume":"20","author":"Choi","year":"2022","journal-title":"Comput. Struct. Biotechnol. J."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/S0308-8146(00)00274-0","article-title":"Inhibitory effects of various antibrowning agents on apple slices","volume":"73","author":"Son","year":"2001","journal-title":"Food Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"135275","DOI":"10.1016\/j.foodchem.2022.135275","article-title":"Synthesis and biological evaluation of new kojic acid-1,3,4-oxadiazole hybrids as tyrosinase inhibitors and their application in the anti-browning of fresh-cut mushrooms","volume":"409","author":"Wang","year":"2023","journal-title":"Food Chem."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Koirala, P., Seong, S.H., Zhou, Y., Shrestha, S., Jung, H.A., and Choi, J.S. (2018). Structure\u2013Activity Relationship of the Tyrosinase Inhibitors Kuwanon G, Mulberrofuran G, and Albanol B from Morus Species: A Kinetics and Molecular Docking Study. Molecules, 23.","DOI":"10.3390\/molecules23061413"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Hwang, Y., Lee, J., Jung, H.J., Ullah, S., Ko, J., Jeong, Y., Park, Y.J., Kang, M.K., Yun, H., and Kim, M.S. (2022). A Novel Class of Potent Anti-Tyrosinase Compounds with Antioxidant Activity, 2-(Substituted phenyl)-5-(trifluoromethyl)benzo[d]thiazoles: In Vitro and In Silico Insights. Antioxidants, 11.","DOI":"10.3390\/antiox11071375"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1016\/j.ejmech.2017.09.059","article-title":"Design, synthesis, kinetic mechanism and molecular docking studies of novel 1-pentanoyl-3-arylthioureas as inhibitors of mushroom tyrosinase and free radical scavengers","volume":"141","author":"Larik","year":"2017","journal-title":"Eur. J. Med. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1007\/s12539-016-0171-x","article-title":"Exploration of Novel Human Tyrosinase Inhibitors by Molecular Modeling, Docking and Simulation Studies","volume":"10","author":"Hassan","year":"2018","journal-title":"Interdiscip. Sci. Comput. Life Sci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"6177","DOI":"10.1021\/jm051256o","article-title":"Extra Precision Glide:\u2009 Docking and Scoring Incorporating a Model of Hydrophobic Enclosure for Protein\u2212Ligand Complexes","volume":"49","author":"Friesner","year":"2006","journal-title":"J. Med. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1080\/07391102.2014.893203","article-title":"A new insight into mushroom tyrosinase inhibitors: Docking, pharmacophore-based virtual screening, and molecular modeling studies","volume":"33","author":"Bagherzadeh","year":"2015","journal-title":"J. Biomol. Struct. Dyn."},{"key":"ref_29","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_30","doi-asserted-by":"crossref","first-page":"1231","DOI":"10.1016\/S0891-5849(98)00315-3","article-title":"Antioxidant activity applying an improved ABTS radical cation decolorization assay","volume":"26","author":"Re","year":"1999","journal-title":"Free Radic. Biol. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1016\/0197-0186(90)90025-O","article-title":"Sensitive and rapid quantitation of oxygen reactive species formation in rat synaptosomes","volume":"17","author":"LeBel","year":"1990","journal-title":"Neurochem. Int."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"823881","DOI":"10.3389\/fphar.2022.823881","article-title":"Role of Phytochemicals in Skin Photoprotection via Regulation of Nrf2","volume":"13","author":"Chaiprasongsuk","year":"2022","journal-title":"Front. Pharmacol."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Htike, T., Saengrayap, R., Aunsri, N., Tontiwattanakul, K., and Chaiwong, S. (2021). Investigation and Evaluation of Impact Bruising in Guava Using Image Processing and Response Surface Methodology. Horticulturae, 7.","DOI":"10.3390\/horticulturae7100411"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1007\/s002170050456","article-title":"Browning susceptibility of minimally processed Baby and Romaine lettuces","volume":"209","author":"Gil","year":"1999","journal-title":"Eur. Food Res. Technol."}],"container-title":["Antioxidants"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3921\/12\/10\/1814\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:02:18Z","timestamp":1760130138000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3921\/12\/10\/1814"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,9,29]]},"references-count":34,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2023,10]]}},"alternative-id":["antiox12101814"],"URL":"https:\/\/doi.org\/10.3390\/antiox12101814","relation":{},"ISSN":["2076-3921"],"issn-type":[{"value":"2076-3921","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,9,29]]}}}