Design, Synthesis, Biological Activity and In Silico Evaluation of Novel Phenylthiazole Derivatives as Multifunctional Skin-Whitening Agents

Design, Synthesis, Biological Activity and In Silico Evaluation of Novel Phenylthiazole Derivatives as Multifunctional Skin-Whitening Agents | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Design, Synthesis, Biological Activity and In Silico Evaluation of Novel Phenylthiazole Derivatives as Multifunctional Skin-Whitening Agents Yang Xu, Xuhui Liang, Chang-Gu Hyun This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7875225/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 15 You are reading this latest preprint version Abstract Excessive melanin accumulation causes hyperpigmentation, a skin pathophysiology that highlights the need for safe and multifunctional skin-whitening agents. Building on the reported tyrosinase inhibitory potential of phenylthiazole derivatives, a series of compounds was designed and synthesized to investigate the structural determinants of their multi-functional activities. The biological evaluation included mushroom tyrosinase (mTYR) inhibition, as well as anti-melanogenic, anti-inflammatory, and antioxidant assays. Among the series, compound 3c exhibited the most potent multi-functional profile, showing mTYR inhibition (IC 50 = 30.8 ± 2.7 µM) with a mixed-type inhibitory mechanism (K i = 20 µM), a 34% reduction in melanin content at 40 µM, significant nitric oxide inhibition (IC 50 = 33.7 ± 2.0 µM), and strong antioxidant activity (SC 50 = 29.0 ± 0.8 µM). Density Functional Theory (DFT) calculations and predicted physicochemical properties indicate that 3c possesses favorable molecular stability and promising potential for skin penetration. Molecular docking and molecular dynamics (MD) simulations further demonstrated that 3c stably occupies the active pocket of human tyrosinase-related protein 1 (TYRP1, PDB ID: 5M8M), forming key interactions with Zn²⁺-coordinating residues and maintaining a stable energetic profile. Collectively, these findings indicate that 3c exhibits the most balanced multi-functional activity within the series and holds promise as a lead compound for topical skin-whitening applications. Phenylthiazole derivatives Tyrosinase inhibition Melanin inhibition Anti-inflammation Antioxidation Molecular docking Molecular dynamics simulations Full Text Additional Declarations No competing interests reported. Supplementary Files supplementarymaterials.docx Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 29 Dec, 2025 Reviews received at journal 20 Dec, 2025 Reviews received at journal 19 Dec, 2025 Reviews received at journal 08 Dec, 2025 Reviewers agreed at journal 07 Dec, 2025 Reviewers agreed at journal 05 Dec, 2025 Reviewers agreed at journal 03 Dec, 2025 Reviewers agreed at journal 03 Dec, 2025 Reviewers agreed at journal 05 Nov, 2025 Reviewers agreed at journal 04 Nov, 2025 Reviewers agreed at journal 04 Nov, 2025 Reviewers invited by journal 03 Nov, 2025 Editor assigned by journal 16 Oct, 2025 Submission checks completed at journal 16 Oct, 2025 First submitted to journal 16 Oct, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7875225","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":540735887,"identity":"ab893a89-94ca-4ef2-bbf1-dd202fe50960","order_by":0,"name":"Yang Xu","email":"","orcid":"","institution":"Jeju Inside Agency and Cosmetic Science Center, Jeju National University","correspondingAuthor":false,"prefix":"","firstName":"Yang","middleName":"","lastName":"Xu","suffix":""},{"id":540735888,"identity":"2f63c12e-be60-414b-8a2d-3e8420aa5a42","order_by":1,"name":"Xuhui Liang","email":"","orcid":"","institution":"Jeju Inside Agency and Cosmetic 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Agents","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"molecular-diversity","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"modi","sideBox":"Learn more about [Molecular Diversity](http://link.springer.com/journal/11030)","snPcode":"11030","submissionUrl":"https://submission.nature.com/new-submission/11030/3","title":"Molecular Diversity","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Phenylthiazole derivatives, Tyrosinase inhibition, Melanin inhibition, Anti-inflammation, Antioxidation, Molecular docking, Molecular dynamics simulations","lastPublishedDoi":"10.21203/rs.3.rs-7875225/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7875225/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eExcessive melanin accumulation causes hyperpigmentation, a skin pathophysiology that highlights the need for safe and multifunctional skin-whitening agents. Building on the reported tyrosinase inhibitory potential of phenylthiazole derivatives, a series of compounds was designed and synthesized to investigate the structural determinants of their multi-functional activities. The biological evaluation included mushroom tyrosinase (mTYR) inhibition, as well as anti-melanogenic, anti-inflammatory, and antioxidant assays. Among the series, compound \u003cb\u003e3c\u003c/b\u003e exhibited the most potent multi-functional profile, showing mTYR inhibition (IC\u003csub\u003e50\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;30.8\u0026thinsp;\u0026plusmn;\u0026thinsp;2.7 \u0026micro;M) with a mixed-type inhibitory mechanism (K\u003csub\u003ei\u003c/sub\u003e = 20 \u0026micro;M), a 34% reduction in melanin content at 40 \u0026micro;M, significant nitric oxide inhibition (IC\u003csub\u003e50\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;33.7\u0026thinsp;\u0026plusmn;\u0026thinsp;2.0 \u0026micro;M), and strong antioxidant activity (SC\u003csub\u003e50\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;29.0\u0026thinsp;\u0026plusmn;\u0026thinsp;0.8 \u0026micro;M). Density Functional Theory (DFT) calculations and predicted physicochemical properties indicate that \u003cb\u003e3c\u003c/b\u003e possesses favorable molecular stability and promising potential for skin penetration. Molecular docking and molecular dynamics (MD) simulations further demonstrated that \u003cb\u003e3c\u003c/b\u003e stably occupies the active pocket of human tyrosinase-related protein 1 (TYRP1, PDB ID: 5M8M), forming key interactions with Zn\u0026sup2;⁺-coordinating residues and maintaining a stable energetic profile. Collectively, these findings indicate that \u003cb\u003e3c\u003c/b\u003e exhibits the most balanced multi-functional activity within the series and holds promise as a lead compound for topical skin-whitening applications.\u003c/p\u003e","manuscriptTitle":"Design, Synthesis, Biological Activity and In Silico Evaluation of Novel Phenylthiazole Derivatives as Multifunctional Skin-Whitening Agents","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-11-13 14:32:25","doi":"10.21203/rs.3.rs-7875225/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-12-29T08:47:41+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-12-21T04:53:53+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-12-19T08:11:02+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-12-08T09:12:02+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"282257386565263362767613218547747093994","date":"2025-12-07T10:32:08+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"44190302641482176716303890096485582942","date":"2025-12-05T08:25:17+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"2238616436290311101841832915281817664","date":"2025-12-04T03:08:17+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"127188621955935056083163807776375872468","date":"2025-12-03T11:53:50+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"328131421112212133020633777977691059338","date":"2025-11-06T04:48:56+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"103531580216065586277715110672928913413","date":"2025-11-04T11:45:06+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"178159950569377089077893765918390295355","date":"2025-11-04T11:04:15+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-11-04T03:21:13+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-10-16T14:16:32+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-10-16T10:32:27+00:00","index":"","fulltext":""},{"type":"submitted","content":"Molecular Diversity","date":"2025-10-16T08:27:26+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"molecular-diversity","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"modi","sideBox":"Learn more about [Molecular Diversity](http://link.springer.com/journal/11030)","snPcode":"11030","submissionUrl":"https://submission.nature.com/new-submission/11030/3","title":"Molecular Diversity","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"32a213b5-9a47-4135-b854-2ed79916e726","owner":[],"postedDate":"November 13th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-03-13T16:38:06+00:00","versionOfRecord":[],"versionCreatedAt":"2025-11-13 14:32:25","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7875225","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7875225","identity":"rs-7875225","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}