Synthesis of N-1′, N-3′-disubstituted spirohydantoins and their anticonvulsant activities in pilocarpine model of temporal lobe epilepsy
[Display omitted] Herein we report the synthesis and anticonvulsant activity of a library of eighteen new compounds that are structural mimics of phenytoin. These class of compounds contain a N-1′, N-3′-disubstituted spirohydantoin scaffold, where the N-1′ and N-3′ positions are modified with an alk...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2016-06, Vol.26 (12), p.2912-2914 |
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| container_issue | 12 |
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| container_title | Bioorganic & medicinal chemistry letters |
| container_volume | 26 |
| creator | Yang, Chen Schanne, Francis A.X. Yoganathan, Sabesan Stephani, Ralph A. |
| description | [Display omitted]
Herein we report the synthesis and anticonvulsant activity of a library of eighteen new compounds that are structural mimics of phenytoin. These class of compounds contain a N-1′, N-3′-disubstituted spirohydantoin scaffold, where the N-1′ and N-3′ positions are modified with an alkyl group or aryl group. Of the eighteen compounds synthesized and tested, compound 5c showed the best anticonvulsant activity. It completely prevented the precursor events of motor seizure in the pilocarpine model of temporal lobe epilepsy. Additionally, ten of the analogs were more effective than phenytoin when compared using the Racine’s score in the pilocarpine model. Based on the structure activity relationship (SAR), we concluded that alkyl groups (ethyl, propyl or cyclopropyl) at N-3′ position and 4-nitro phenyl group at N-1′ position are desirable. |
| doi_str_mv | 10.1016/j.bmcl.2016.04.040 |
| format | Article |
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Herein we report the synthesis and anticonvulsant activity of a library of eighteen new compounds that are structural mimics of phenytoin. These class of compounds contain a N-1′, N-3′-disubstituted spirohydantoin scaffold, where the N-1′ and N-3′ positions are modified with an alkyl group or aryl group. Of the eighteen compounds synthesized and tested, compound 5c showed the best anticonvulsant activity. It completely prevented the precursor events of motor seizure in the pilocarpine model of temporal lobe epilepsy. Additionally, ten of the analogs were more effective than phenytoin when compared using the Racine’s score in the pilocarpine model. Based on the structure activity relationship (SAR), we concluded that alkyl groups (ethyl, propyl or cyclopropyl) at N-3′ position and 4-nitro phenyl group at N-1′ position are desirable.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2016.04.040</identifier><identifier>PMID: 27133483</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>Animals ; Anticonvulsant ; Anticonvulsants - chemical synthesis ; Anticonvulsants - chemistry ; Anticonvulsants - pharmacology ; Dose-Response Relationship, Drug ; Epilepsy ; Epilepsy, Temporal Lobe - drug therapy ; Molecular Structure ; N,N′-Disubstituted ureas ; Pilocarpine - chemical synthesis ; Pilocarpine - chemistry ; Pilocarpine - pharmacology ; Rats ; Seizure ; Seizures - drug therapy ; Spiro Compounds - chemical synthesis ; Spiro Compounds - chemistry ; Spiro Compounds - pharmacology ; Spirohydantoin ; Structure-Activity Relationship</subject><ispartof>Bioorganic & medicinal chemistry letters, 2016-06, Vol.26 (12), p.2912-2914</ispartof><rights>2016 Elsevier Ltd</rights><rights>Copyright © 2016 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c389t-b0eb3af39b09f85f487730004e08ecedd171df6f8e1395e5a8f0f556590f646b3</citedby><cites>FETCH-LOGICAL-c389t-b0eb3af39b09f85f487730004e08ecedd171df6f8e1395e5a8f0f556590f646b3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0960894X16304139$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3536,27903,27904,65309</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27133483$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Yang, Chen</creatorcontrib><creatorcontrib>Schanne, Francis A.X.</creatorcontrib><creatorcontrib>Yoganathan, Sabesan</creatorcontrib><creatorcontrib>Stephani, Ralph A.</creatorcontrib><title>Synthesis of N-1′, N-3′-disubstituted spirohydantoins and their anticonvulsant activities in pilocarpine model of temporal lobe epilepsy</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>[Display omitted]
Herein we report the synthesis and anticonvulsant activity of a library of eighteen new compounds that are structural mimics of phenytoin. These class of compounds contain a N-1′, N-3′-disubstituted spirohydantoin scaffold, where the N-1′ and N-3′ positions are modified with an alkyl group or aryl group. Of the eighteen compounds synthesized and tested, compound 5c showed the best anticonvulsant activity. It completely prevented the precursor events of motor seizure in the pilocarpine model of temporal lobe epilepsy. Additionally, ten of the analogs were more effective than phenytoin when compared using the Racine’s score in the pilocarpine model. Based on the structure activity relationship (SAR), we concluded that alkyl groups (ethyl, propyl or cyclopropyl) at N-3′ position and 4-nitro phenyl group at N-1′ position are desirable.</description><subject>Animals</subject><subject>Anticonvulsant</subject><subject>Anticonvulsants - chemical synthesis</subject><subject>Anticonvulsants - chemistry</subject><subject>Anticonvulsants - pharmacology</subject><subject>Dose-Response Relationship, Drug</subject><subject>Epilepsy</subject><subject>Epilepsy, Temporal Lobe - drug therapy</subject><subject>Molecular Structure</subject><subject>N,N′-Disubstituted ureas</subject><subject>Pilocarpine - chemical synthesis</subject><subject>Pilocarpine - chemistry</subject><subject>Pilocarpine - pharmacology</subject><subject>Rats</subject><subject>Seizure</subject><subject>Seizures - drug therapy</subject><subject>Spiro Compounds - chemical synthesis</subject><subject>Spiro Compounds - chemistry</subject><subject>Spiro Compounds - pharmacology</subject><subject>Spirohydantoin</subject><subject>Structure-Activity Relationship</subject><issn>0960-894X</issn><issn>1464-3405</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkc2KFDEUhYMoTjv6Ai4kSxdWe9NJqlLgRobxBwZdqOAupJIbJk1VpUxSDb3zAXwaH8knMU2PLhUunLv4zgk3h5CnDLYMWPtyvx0mO253dd-CqAP3yIaJVjRcgLxPNtC30KhefL0gj3LeAzABQjwkF7uOcS4U35Afn45zucUcMo2efmjYr-8_X1TlVRsX8jrkEspa0NG8hBRvj87MJYY5UzM7Wq0h1a0EG-fDOua6UmNLOIQSMNMw0yWM0Zq0hBnpFB2Op4cKTktMZqRjHJBiZXDJx8fkgTdjxid3ekm-vLn-fPWuufn49v3V65vGctWXZgAcuPG8H6D3Snqhuo4DgEBQaNE51jHnW6-Q8V6iNMqDl7KVPfhWtAO_JM_PuUuK31bMRU8hWxxHM2Ncs2YKVAeyU7v_o13Pd0xKkBXdnVGbYs4JvV5SmEw6agb6VJje61Nh-lSYBlEHqunZXf46TOj-Wv40VIFXZwDrhxwCJp1twLmeGRLaol0M_8r_DVD7q04</recordid><startdate>20160615</startdate><enddate>20160615</enddate><creator>Yang, Chen</creator><creator>Schanne, Francis A.X.</creator><creator>Yoganathan, Sabesan</creator><creator>Stephani, Ralph A.</creator><general>Elsevier Ltd</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>7QO</scope><scope>7TK</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope></search><sort><creationdate>20160615</creationdate><title>Synthesis of N-1′, N-3′-disubstituted spirohydantoins and their anticonvulsant activities in pilocarpine model of temporal lobe epilepsy</title><author>Yang, Chen ; Schanne, Francis A.X. ; Yoganathan, Sabesan ; Stephani, Ralph A.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c389t-b0eb3af39b09f85f487730004e08ecedd171df6f8e1395e5a8f0f556590f646b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Animals</topic><topic>Anticonvulsant</topic><topic>Anticonvulsants - chemical synthesis</topic><topic>Anticonvulsants - chemistry</topic><topic>Anticonvulsants - pharmacology</topic><topic>Dose-Response Relationship, Drug</topic><topic>Epilepsy</topic><topic>Epilepsy, Temporal Lobe - drug therapy</topic><topic>Molecular Structure</topic><topic>N,N′-Disubstituted ureas</topic><topic>Pilocarpine - chemical synthesis</topic><topic>Pilocarpine - chemistry</topic><topic>Pilocarpine - pharmacology</topic><topic>Rats</topic><topic>Seizure</topic><topic>Seizures - drug therapy</topic><topic>Spiro Compounds - chemical synthesis</topic><topic>Spiro Compounds - chemistry</topic><topic>Spiro Compounds - pharmacology</topic><topic>Spirohydantoin</topic><topic>Structure-Activity Relationship</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Yang, Chen</creatorcontrib><creatorcontrib>Schanne, Francis A.X.</creatorcontrib><creatorcontrib>Yoganathan, Sabesan</creatorcontrib><creatorcontrib>Stephani, Ralph A.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>Biotechnology Research Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><jtitle>Bioorganic & medicinal chemistry letters</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Yang, Chen</au><au>Schanne, Francis A.X.</au><au>Yoganathan, Sabesan</au><au>Stephani, Ralph A.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Synthesis of N-1′, N-3′-disubstituted spirohydantoins and their anticonvulsant activities in pilocarpine model of temporal lobe epilepsy</atitle><jtitle>Bioorganic & medicinal chemistry letters</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>2016-06-15</date><risdate>2016</risdate><volume>26</volume><issue>12</issue><spage>2912</spage><epage>2914</epage><pages>2912-2914</pages><issn>0960-894X</issn><eissn>1464-3405</eissn><abstract>[Display omitted]
Herein we report the synthesis and anticonvulsant activity of a library of eighteen new compounds that are structural mimics of phenytoin. These class of compounds contain a N-1′, N-3′-disubstituted spirohydantoin scaffold, where the N-1′ and N-3′ positions are modified with an alkyl group or aryl group. Of the eighteen compounds synthesized and tested, compound 5c showed the best anticonvulsant activity. It completely prevented the precursor events of motor seizure in the pilocarpine model of temporal lobe epilepsy. Additionally, ten of the analogs were more effective than phenytoin when compared using the Racine’s score in the pilocarpine model. Based on the structure activity relationship (SAR), we concluded that alkyl groups (ethyl, propyl or cyclopropyl) at N-3′ position and 4-nitro phenyl group at N-1′ position are desirable.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>27133483</pmid><doi>10.1016/j.bmcl.2016.04.040</doi><tpages>3</tpages></addata></record> |
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| source | MEDLINE; Elsevier ScienceDirect Journals |
| subjects | Animals Anticonvulsant Anticonvulsants - chemical synthesis Anticonvulsants - chemistry Anticonvulsants - pharmacology Dose-Response Relationship, Drug Epilepsy Epilepsy, Temporal Lobe - drug therapy Molecular Structure N,N′-Disubstituted ureas Pilocarpine - chemical synthesis Pilocarpine - chemistry Pilocarpine - pharmacology Rats Seizure Seizures - drug therapy Spiro Compounds - chemical synthesis Spiro Compounds - chemistry Spiro Compounds - pharmacology Spirohydantoin Structure-Activity Relationship |
| title | Synthesis of N-1′, N-3′-disubstituted spirohydantoins and their anticonvulsant activities in pilocarpine model of temporal lobe epilepsy |
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