Rational Design and In Silico Evaluation of Benzimidazole-Fused Pyran Derivatives as Acetylcholinesterase Inhibitors for Alzheimer’s Disease

Rational Design and In Silico Evaluation of Benzimidazole-Fused Pyran Derivatives as Acetylcholinesterase Inhibitors for Alzheimer’s Disease | 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 Rational Design and In Silico Evaluation of Benzimidazole-Fused Pyran Derivatives as Acetylcholinesterase Inhibitors for Alzheimer’s Disease Shivank Sharma, Vanktesh Kumar, Stalin Arulsamy, Pankaj Wadhwa, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8993822/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 13 You are reading this latest preprint version Abstract Alzheimer’s disease (AD) is a progressive neurodegenerative disorder marked by cholinergic dysfunction, for which acetylcholinesterase (AChE) inhibition remains a clinically validated symptomatic treatment strategy. In the present study, a series of benzimidazole-dihydropyran hybrid derivatives ( 4a-n ) were rationally designed and evaluated using an integrated computational workflow to identify promising AChE inhibitors. Molecular docking demonstrated favorable binding of several derivatives within both the catalytic active site and peripheral anionic site of AChE, stabilized by π-π stacking, hydrogen bonding, and hydrophobic interactions with key residues. ADMET profiling predicted acceptable oral bioavailability, blood-brain barrier permeability, and drug-like properties for the prioritized compounds. Density functional theory analysis revealed that the most active candidates possessed narrow HOMO-LUMO energy gaps, indicating enhanced electronic complementarity and charge-transfer capability within the AChE binding gorge. Machine learning-assisted QSAR modeling further supported the activity trends and highlighted compounds 4b, 4c, 4f , and 4i as the most promising leads. These results establish the benzimidazole-dihydropyran scaffold as a viable platform for the development of next-generation AChE inhibitors and provide a robust computational basis for subsequent experimental validation toward Alzheimer’s disease therapy. Acetylcholinesterase inhibitors Benzimidazole-dihydropyran hybrids Alzheimer’s disease Structure-based drug design Machine learning-assisted QSAR Full Text Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Review Version 1 posted Reviews received at journal 16 Apr, 2026 Reviews received at journal 15 Apr, 2026 Reviewers agreed at journal 15 Apr, 2026 Reviewers agreed at journal 14 Apr, 2026 Reviews received at journal 12 Apr, 2026 Reviewers agreed at journal 12 Apr, 2026 Reviewers agreed at journal 10 Apr, 2026 Reviewers agreed at journal 09 Apr, 2026 Reviewers agreed at journal 09 Apr, 2026 Reviewers invited by journal 09 Apr, 2026 Editor assigned by journal 03 Mar, 2026 Submission checks completed at journal 03 Mar, 2026 First submitted to journal 28 Feb, 2026 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-8993822","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":624144950,"identity":"69f3b7d4-c579-4ee6-b4bf-f3d27429ad64","order_by":0,"name":"Shivank Sharma","email":"","orcid":"","institution":"Lovely Professional University","correspondingAuthor":false,"prefix":"","firstName":"Shivank","middleName":"","lastName":"Sharma","suffix":""},{"id":624144951,"identity":"6622057b-dbd6-4bf3-b3ce-9f01304155e1","order_by":1,"name":"Vanktesh Kumar","email":"","orcid":"","institution":"Lovely Professional University","correspondingAuthor":false,"prefix":"","firstName":"Vanktesh","middleName":"","lastName":"Kumar","suffix":""},{"id":624144952,"identity":"71acbcb0-04f9-4640-a9b8-0769c892126a","order_by":2,"name":"Stalin Arulsamy","email":"","orcid":"","institution":"Lovely Professional University","correspondingAuthor":false,"prefix":"","firstName":"Stalin","middleName":"","lastName":"Arulsamy","suffix":""},{"id":624144953,"identity":"f7fab81a-5664-47c0-a8c9-b733106325b0","order_by":3,"name":"Pankaj Wadhwa","email":"","orcid":"","institution":"Ummeed Institute of Pharmaceutical Sciences and Research Center,Khatlabana","correspondingAuthor":false,"prefix":"","firstName":"Pankaj","middleName":"","lastName":"Wadhwa","suffix":""},{"id":624144954,"identity":"2a052446-07aa-477c-b2e7-a2af92df683d","order_by":4,"name":"Shubham Kumar","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA6ElEQVRIiWNgGAWjYBAC+RkMbMwghv39h40PgDQPHyEtBjegWhgOJDcbgLSwEdQiAdeS3iYBoglrke4xe1xQsy2aseFgW+XXHDsZNgbmh49u4PPLnDPmxjOO3c5tZmxsuy27LRnoMDZj4xx81tzIMZPmYbud28bM2HZbchszUAsPmzRhLf9u5/awMbYVS26rJ1ILb9vt3Bk8jG2MH7cdJqzF4EZauTFv3+3cDRKMzdKM247zsDET8Iv8jORtj3m+gbSwP/z4c1u1PT9788PHeB2GDJh5wCSxykGA8QcpqkfBKBgFo2DEAABmtEgWSNOmBQAAAABJRU5ErkJggg==","orcid":"","institution":"Lovely Professional University","correspondingAuthor":true,"prefix":"","firstName":"Shubham","middleName":"","lastName":"Kumar","suffix":""}],"badges":[],"createdAt":"2026-02-28 09:24:07","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8993822/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8993822/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":107482326,"identity":"3621b3b5-55bf-41a9-9210-2e79b9df3962","added_by":"auto","created_at":"2026-04-22 02:23:12","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1233140,"visible":true,"origin":"","legend":"","description":"","filename":"BENIMIDAZOLEFURANManuscriptfinalversionAChE.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8993822/v1_covered_0d9e96aa-da66-476d-a454-7f5af62b90b6.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Rational Design and In Silico Evaluation of Benzimidazole-Fused Pyran Derivatives as Acetylcholinesterase Inhibitors for Alzheimer’s Disease","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"chemical-papers","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"chpa","sideBox":"Learn more about [Chemical Papers](http://link.springer.com/journal/11696)","snPcode":"11696","submissionUrl":"https://www.editorialmanager.com/CHPA/default.aspx","title":"Chemical Papers","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Acetylcholinesterase inhibitors, Benzimidazole-dihydropyran hybrids, Alzheimer’s disease, Structure-based drug design, Machine learning-assisted QSAR","lastPublishedDoi":"10.21203/rs.3.rs-8993822/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8993822/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eAlzheimer\u0026rsquo;s disease (AD) is a progressive neurodegenerative disorder marked by cholinergic dysfunction, for which acetylcholinesterase (AChE) inhibition remains a clinically validated symptomatic treatment strategy. In the present study, a series of benzimidazole-dihydropyran hybrid derivatives (\u003cb\u003e4a-n\u003c/b\u003e) were rationally designed and evaluated using an integrated computational workflow to identify promising AChE inhibitors. Molecular docking demonstrated favorable binding of several derivatives within both the catalytic active site and peripheral anionic site of AChE, stabilized by π-π stacking, hydrogen bonding, and hydrophobic interactions with key residues. ADMET profiling predicted acceptable oral bioavailability, blood-brain barrier permeability, and drug-like properties for the prioritized compounds. Density functional theory analysis revealed that the most active candidates possessed narrow HOMO-LUMO energy gaps, indicating enhanced electronic complementarity and charge-transfer capability within the AChE binding gorge. Machine learning-assisted QSAR modeling further supported the activity trends and highlighted compounds \u003cb\u003e4b, 4c, 4f\u003c/b\u003e, and \u003cb\u003e4i\u003c/b\u003e as the most promising leads. These results establish the benzimidazole-dihydropyran scaffold as a viable platform for the development of next-generation AChE inhibitors and provide a robust computational basis for subsequent experimental validation toward Alzheimer\u0026rsquo;s disease therapy.\u003c/p\u003e","manuscriptTitle":"Rational Design and In Silico Evaluation of Benzimidazole-Fused Pyran Derivatives as Acetylcholinesterase Inhibitors for Alzheimer’s Disease","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-04-17 09:06:42","doi":"10.21203/rs.3.rs-8993822/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"","date":"2026-04-16T08:17:27+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-15T15:05:30+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"290744619021311174583256148357897716439","date":"2026-04-15T13:16:09+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"251867014369711554839949965688475833515","date":"2026-04-14T09:57:21+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-12T07:07:43+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"252902270951743347650335936788919324389","date":"2026-04-12T06:02:59+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"35363942968042602882572308071100793231","date":"2026-04-10T05:48:43+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"169634528291428011673067170945442945593","date":"2026-04-10T03:31:00+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"3873780614573169071442268312245805912","date":"2026-04-09T23:36:24+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-04-09T18:29:33+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-03-03T16:10:53+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-03-03T14:37:58+00:00","index":"","fulltext":""},{"type":"submitted","content":"Chemical Papers","date":"2026-02-28T09:17:41+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"chemical-papers","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"chpa","sideBox":"Learn more about [Chemical Papers](http://link.springer.com/journal/11696)","snPcode":"11696","submissionUrl":"https://www.editorialmanager.com/CHPA/default.aspx","title":"Chemical Papers","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"51e086f4-78fd-420b-a4f1-bad283f6a5bc","owner":[],"postedDate":"April 17th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-04-17T09:06:42+00:00","versionOfRecord":[],"versionCreatedAt":"2026-04-17 09:06:42","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8993822","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8993822","identity":"rs-8993822","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}