Study the Structure and Dynamics of Antifungal Agent Ketoconazole by CSA and Site-Specific Spin-Lattice Relaxation Time Measurements

Study the Structure and Dynamics of Antifungal Agent Ketoconazole by CSA and Site-Specific Spin-Lattice Relaxation Time Measurements | 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 Study the Structure and Dynamics of Antifungal Agent Ketoconazole by CSA and Site-Specific Spin-Lattice Relaxation Time Measurements Krishna Kishor Dey, Manasi Ghosh This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-275524/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract An azole antifungal agent, ketoconazole, is widely used in the treatment of mucosal fungal infections related to AIDS immunosuppression, organ transplantation, and cancer chemotherapy. The structure and dynamics of ketoconazole are thoroughly studied by chemical shift anisotropy tensor and site-specific spin-lattice relaxation time measurements. The molecular correlation time at crystallographically different carbon sites is calculated by considering that the spin-lattice relaxation mechanism for the 13C nucleus is mainly governed by chemical shift anisotropy interaction and hetero-nuclear dipole-dipole coupling. The CSA parameters at the crystallographically distinct sites of ketoconazole are determined by two-dimensional phase adjusted spinning sideband (2D PASS) cross-polarization magic angle spinning (CP-MAS) solid-state NMR experiment. The site-specific spin-lattice relaxation time is measured by the Torchia CP experiment. The spin-lattice relaxation rate is slow for all the carbon nuclei sites except C2, C3, C4, C5, and C26 carbon nuclei reside on the piperazine ring and the methyl group. It suggests the close-pack arrangement of the molecule due to π-π stacking interaction. The molecular correlation time of all the carbon atoms reside on the benzene ring, 1,3-dioxolane ring, imidazole ring, and the 2,4-dichlorobenzene ring is of the order of 10-4 s, while it is of the order of 10-7 s for carbon atoms reside on the piperazine ring. The CSA parameters of the carbon nuclei on the piperazine ring (C2, C3, C4, C5), and the methyl group (C26) are very low compared to other carbon nuclei. The CSA parameters are very high for carbon nuclei reside on the benzene ring, imidazole ring, and the 2,4-dichlorobenzene ring due to the presence of π-electrons. A huge variation of the spin-lattice relaxation time and the molecular correlation time are observed for numerous carbon nuclei situated on the side-chain of ketoconazole. The spin-lattice relaxation time varies from 500 s to 8 s, and the molecular correlation time varies in the range of 10-4s to 10-7s. These types of investigations portrayed the correlation between the structure and dynamics of the antifungal drug ketoconazole, which will help to develop the advanced antifungal drugs. Additionally, the CSA information of the drug molecules will be immensely useful for NMR crystallography. Biomaterials Systems Biology General Biochemistry antifungal agent immunosuppression azole Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Full Text Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted 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. 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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-275524","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":14607025,"identity":"f2dacfb3-dd5f-48ee-8e53-16f602532b53","order_by":0,"name":"Krishna Kishor Dey","email":"","orcid":"","institution":"Dr. Hari Singh Gour University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Krishna","middleName":"Kishor","lastName":"Dey","suffix":""},{"id":14607026,"identity":"cb6b19c9-2f89-4736-bf6e-c9a78e97e4a0","order_by":1,"name":"Manasi Ghosh","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA7klEQVRIiWNgGAWjYNACAzBiY/jYcAAikECsFsaZxGuB6GJj5oVpwQd0288e/PijgMFuO3v7s8e2O+4kNrAffsDwcAduLWZn8pKleQwYknf2nDE3zj3zLLGBJ82AIfEMHi0Hcgykga5KNriRwyad23Y4sYEhh4EhsQ2PlvNvjH/+AGtJfyZtCdLC/4aAlhs5ZhJAh9kZ3Egwk2YEaZEgZMuNN2bWPAYSCQZnzphJ9p45bNwm8czgAH6H5Rjf/PHHxt7gePsziZ87Dsv28yc/fPgTjxYokAD6GgrYgPgAQQ1AYE+MolEwCkbBKBihAADvaFSXeGzSkgAAAABJRU5ErkJggg==","orcid":"","institution":"Banaras Hindu University","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Manasi","middleName":"","lastName":"Ghosh","suffix":""}],"badges":[],"createdAt":"2021-02-25 06:29:10","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-275524/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-275524/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":6858728,"identity":"8e6d1ef3-7fd4-4e9e-b008-7c7efedbbf6a","added_by":"auto","created_at":"2021-03-11 21:09:03","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":108754,"visible":true,"origin":"","legend":"(a) Chemical structure of ketoconazole molecule. It is associated with five rings – piperazine ring, benzene ring, 1,3-dioxolane ring, imidazole ring, and 2,4-dichlorobenzene ring. It forms a close-pack arrangement by π…π stacking interaction. (b) 13C CP-MAS NMR spectrum of ketoconazole.","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-275524/v1/6c1625f31fd1f53caa1775ff.jpg"},{"id":6859073,"identity":"5c784973-eb24-47eb-94e8-40e96ecc72c0","added_by":"auto","created_at":"2021-03-11 21:12:03","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":60819,"visible":true,"origin":"","legend":"13C 2DPASS CP-MAS NMR spectrum of ketoconazole. Direct dimension represents infinite spinning speed spectrum, and the indirect dimension represents chemical shift anisotropy spectrum.","description":"","filename":"2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-275524/v1/707337889e4baf78dda58535.jpg"},{"id":6858730,"identity":"9e3d1977-1ab7-4ab9-883d-9f10da75d07d","added_by":"auto","created_at":"2021-03-11 21:09:03","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":129053,"visible":true,"origin":"","legend":"Spinning CSA sideband pattern of crystallographically different carbon sites of ketoconazole.","description":"","filename":"3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-275524/v1/bb93301d389605b306385fe5.jpg"},{"id":6859072,"identity":"c62e81c4-2955-484d-aadc-42944ee4d226","added_by":"auto","created_at":"2021-03-11 21:12:03","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":101289,"visible":true,"origin":"","legend":"Spinning CSA sideband pattern of crystallographically different carbon sites of ketoconazole.","description":"","filename":"4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-275524/v1/98f058fe8c67c6083b971427.jpg"},{"id":6859396,"identity":"02090cfe-ea79-494e-91c3-bf37e34c12bc","added_by":"auto","created_at":"2021-03-11 21:15:03","extension":"jpg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":107763,"visible":true,"origin":"","legend":"The bar-diagram of (a) anisotropy and (b) asymmetry parameter of ketoconazole.","description":"","filename":"5.jpg","url":"https://assets-eu.researchsquare.com/files/rs-275524/v1/98f1423b9e3e23937735bc7e.jpg"},{"id":6858734,"identity":"8b6c9a51-e98f-4760-9437-3e1fe8ee299c","added_by":"auto","created_at":"2021-03-11 21:09:03","extension":"jpg","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":112287,"visible":true,"origin":"","legend":"The longitudinal magnetization decay curves at (a) C1, (b) C9, (c) C6, and (d) C23, C25 nuclei sites of ketoconazole. (e) Bar-diagram of spin-lattice relaxation time at chemically different carbon nuclei sites of ketoconazole.","description":"","filename":"6.jpg","url":"https://assets-eu.researchsquare.com/files/rs-275524/v1/42195108eebcdfbd798a4b40.jpg"},{"id":6859395,"identity":"f464595b-e362-4072-94d9-41e8d44e85fd","added_by":"auto","created_at":"2021-03-11 21:15:03","extension":"jpg","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":48298,"visible":true,"origin":"","legend":"Bar-diagram of molecular correlation time at various carbon nuclei sites of ketoconazole.","description":"","filename":"7.jpg","url":"https://assets-eu.researchsquare.com/files/rs-275524/v1/e386b40e915b1f6b7304f7dc.jpg"},{"id":13603063,"identity":"c7a30930-6b89-4e10-8bb4-08c5eddd69f8","added_by":"auto","created_at":"2021-09-17 05:54:00","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1134286,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-275524/v1_covered.pdf"},{"id":6859911,"identity":"90512e89-987b-437f-99b8-6e4010824888","added_by":"auto","created_at":"2021-03-11 21:18:24","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":762038,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-275524/v1_stamped.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Study the Structure and Dynamics of Antifungal Agent Ketoconazole by CSA and Site-Specific Spin-Lattice Relaxation Time Measurements","fulltext":[{"header":"Full Text","content":"\u003cp\u003eThis preprint is available for \u003ca href='/article/rs-275524/latest.pdf' target='_blank'\u003edownload as a PDF\u003c/a\u003e.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"antifungal agent, immunosuppression, azole","lastPublishedDoi":"10.21203/rs.3.rs-275524/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-275524/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"An azole antifungal agent, ketoconazole, is widely used in the treatment of mucosal fungal infections related to AIDS immunosuppression, organ transplantation, and cancer chemotherapy. The structure and dynamics of ketoconazole are thoroughly studied by chemical shift anisotropy tensor and site-specific spin-lattice relaxation time measurements. The molecular correlation time at crystallographically different carbon sites is calculated by considering that the spin-lattice relaxation mechanism for the 13C nucleus is mainly governed by chemical shift anisotropy interaction and hetero-nuclear dipole-dipole coupling. The CSA parameters at the crystallographically distinct sites of ketoconazole are determined by two-dimensional phase adjusted spinning sideband (2D PASS) cross-polarization magic angle spinning (CP-MAS) solid-state NMR experiment. The site-specific spin-lattice relaxation time is measured by the Torchia CP experiment. The spin-lattice relaxation rate is slow for all the carbon nuclei sites except C2, C3, C4, C5, and C26 carbon nuclei reside on the piperazine ring and the methyl group. It suggests the close-pack arrangement of the molecule due to π-π stacking interaction. The molecular correlation time of all the carbon atoms reside on the benzene ring, 1,3-dioxolane ring, imidazole ring, and the 2,4-dichlorobenzene ring is of the order of 10-4 s, while it is of the order of 10-7 s for carbon atoms reside on the piperazine ring. The CSA parameters of the carbon nuclei on the piperazine ring (C2, C3, C4, C5), and the methyl group (C26) are very low compared to other carbon nuclei. The CSA parameters are very high for carbon nuclei reside on the benzene ring, imidazole ring, and the 2,4-dichlorobenzene ring due to the presence of π-electrons. A huge variation of the spin-lattice relaxation time and the molecular correlation time are observed for numerous carbon nuclei situated on the side-chain of ketoconazole. The spin-lattice relaxation time varies from 500 s to 8 s, and the molecular correlation time varies in the range of 10-4s to 10-7s. These types of investigations portrayed the correlation between the structure and dynamics of the antifungal drug ketoconazole, which will help to develop the advanced antifungal drugs. Additionally, the CSA information of the drug molecules will be immensely useful for NMR crystallography.","manuscriptTitle":"Study the Structure and Dynamics of Antifungal Agent Ketoconazole by CSA and Site-Specific Spin-Lattice Relaxation Time Measurements","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2021-03-11 21:09:01","doi":"10.21203/rs.3.rs-275524/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"0f2da9f0-29b5-4567-9d39-ac739d034fd8","owner":[],"postedDate":"March 11th, 2021","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":2915303,"name":"Biomaterials"},{"id":2915304,"name":"Systems Biology"},{"id":2915305,"name":"General Biochemistry"}],"tags":[],"updatedAt":"2021-03-18T06:44:08+00:00","versionOfRecord":[],"versionCreatedAt":"2021-03-11 21:09:01","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-275524","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-275524","identity":"rs-275524","version":["v1"]},"buildId":"7rjqhiLT3MXkJMwkYKINL","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}