Synthesis and characterization of novel oxazines and demonstration that they specifically target cyclooxygenase 2
[Display omitted] In the present study, we used solution combustion synthesis-bismuth oxide (Bi2O3) as catalyst for the simple and efficient synthesis of 1,2-oxazine based derivatives of 6-fluoro-3-(piperidin-4-yl)benzo[d]isoxazoles, 1-arylpiperazine and carbazoles. (4aR,8aR)-4-(4-Methoxyphenyl)-3-(...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2015-08, Vol.25 (15), p.2931-2936 |
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| creator | Srinivas, V. Mohan, Chakrabhavi Dhananjaya Baburajeev, C.P. Rangappa, Shobith Jagadish, Swamy Fuchs, Julian E. Sukhorukov, Alexey Yu Chandra Mason, Daniel J. Sharath Kumar, Kothanahally Shivaramu Madegowda, Mahendra Bender, Andreas Basappa Rangappa, Kanchugarakoppal Subbegowda |
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In the present study, we used solution combustion synthesis-bismuth oxide (Bi2O3) as catalyst for the simple and efficient synthesis of 1,2-oxazine based derivatives of 6-fluoro-3-(piperidin-4-yl)benzo[d]isoxazoles, 1-arylpiperazine and carbazoles. (4aR,8aR)-4-(4-Methoxyphenyl)-3-((4-(4-methoxyphenyl)piperazin-1-yl)methyl)-4a,5,6,7,8,8a-hexahydro-4H-benzo[e][1,2]oxazine was found to be the most potent compound with a high degree of selectivity in inhibition towards COX2 (1.7μM) over COX1 (40.4μM) demonstrating the significance of 1,2-oxazine derivatives in developing COX2 specific inhibitors. Molecular docking analyses demonstrated that an isoleucine residue in the active site of COX1 is responsible for lower affinity to COX1 and increased potency towards COX2. Overall, our study reveals that the new 1,2-oxazine-based small molecules qualify as lead structures in developing COX2-specific inhibitors for anti-inflammatory therapy. |
| doi_str_mv | 10.1016/j.bmcl.2015.05.047 |
| format | Article |
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In the present study, we used solution combustion synthesis-bismuth oxide (Bi2O3) as catalyst for the simple and efficient synthesis of 1,2-oxazine based derivatives of 6-fluoro-3-(piperidin-4-yl)benzo[d]isoxazoles, 1-arylpiperazine and carbazoles. (4aR,8aR)-4-(4-Methoxyphenyl)-3-((4-(4-methoxyphenyl)piperazin-1-yl)methyl)-4a,5,6,7,8,8a-hexahydro-4H-benzo[e][1,2]oxazine was found to be the most potent compound with a high degree of selectivity in inhibition towards COX2 (1.7μM) over COX1 (40.4μM) demonstrating the significance of 1,2-oxazine derivatives in developing COX2 specific inhibitors. Molecular docking analyses demonstrated that an isoleucine residue in the active site of COX1 is responsible for lower affinity to COX1 and increased potency towards COX2. Overall, our study reveals that the new 1,2-oxazine-based small molecules qualify as lead structures in developing COX2-specific inhibitors for anti-inflammatory therapy.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2015.05.047</identifier><identifier>PMID: 26048794</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>Anti-Inflammatory Agents - chemical synthesis ; Anti-Inflammatory Agents - chemistry ; Anti-Inflammatory Agents - pharmacology ; COX2 ; Cyclooxygenase 2 - chemistry ; Cyclooxygenase 2 - immunology ; Cyclooxygenase 2 Inhibitors - chemical synthesis ; Cyclooxygenase 2 Inhibitors - chemistry ; Cyclooxygenase 2 Inhibitors - pharmacology ; Humans ; Inflammation - drug therapy ; Inflammation - enzymology ; Inflammation - immunology ; Molecular Docking Simulation ; Oxazines ; Oxazines - chemical synthesis ; Oxazines - chemistry ; Oxazines - pharmacology ; Proinflammatory disease ; SCS-Bi2O3</subject><ispartof>Bioorganic & medicinal chemistry letters, 2015-08, Vol.25 (15), p.2931-2936</ispartof><rights>2015 Elsevier Ltd</rights><rights>Copyright © 2015 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c470t-ea9c41c5defe9f1267fd7185eea1c74f2a3e7f2026026448089f16db9f4af6e83</citedby><cites>FETCH-LOGICAL-c470t-ea9c41c5defe9f1267fd7185eea1c74f2a3e7f2026026448089f16db9f4af6e83</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.bmcl.2015.05.047$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26048794$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Srinivas, V.</creatorcontrib><creatorcontrib>Mohan, Chakrabhavi Dhananjaya</creatorcontrib><creatorcontrib>Baburajeev, C.P.</creatorcontrib><creatorcontrib>Rangappa, Shobith</creatorcontrib><creatorcontrib>Jagadish, Swamy</creatorcontrib><creatorcontrib>Fuchs, Julian E.</creatorcontrib><creatorcontrib>Sukhorukov, Alexey Yu</creatorcontrib><creatorcontrib>Chandra</creatorcontrib><creatorcontrib>Mason, Daniel J.</creatorcontrib><creatorcontrib>Sharath Kumar, Kothanahally Shivaramu</creatorcontrib><creatorcontrib>Madegowda, Mahendra</creatorcontrib><creatorcontrib>Bender, Andreas</creatorcontrib><creatorcontrib>Basappa</creatorcontrib><creatorcontrib>Rangappa, Kanchugarakoppal Subbegowda</creatorcontrib><title>Synthesis and characterization of novel oxazines and demonstration that they specifically target cyclooxygenase 2</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>[Display omitted]
In the present study, we used solution combustion synthesis-bismuth oxide (Bi2O3) as catalyst for the simple and efficient synthesis of 1,2-oxazine based derivatives of 6-fluoro-3-(piperidin-4-yl)benzo[d]isoxazoles, 1-arylpiperazine and carbazoles. (4aR,8aR)-4-(4-Methoxyphenyl)-3-((4-(4-methoxyphenyl)piperazin-1-yl)methyl)-4a,5,6,7,8,8a-hexahydro-4H-benzo[e][1,2]oxazine was found to be the most potent compound with a high degree of selectivity in inhibition towards COX2 (1.7μM) over COX1 (40.4μM) demonstrating the significance of 1,2-oxazine derivatives in developing COX2 specific inhibitors. Molecular docking analyses demonstrated that an isoleucine residue in the active site of COX1 is responsible for lower affinity to COX1 and increased potency towards COX2. Overall, our study reveals that the new 1,2-oxazine-based small molecules qualify as lead structures in developing COX2-specific inhibitors for anti-inflammatory therapy.</description><subject>Anti-Inflammatory Agents - chemical synthesis</subject><subject>Anti-Inflammatory Agents - chemistry</subject><subject>Anti-Inflammatory Agents - pharmacology</subject><subject>COX2</subject><subject>Cyclooxygenase 2 - chemistry</subject><subject>Cyclooxygenase 2 - immunology</subject><subject>Cyclooxygenase 2 Inhibitors - chemical synthesis</subject><subject>Cyclooxygenase 2 Inhibitors - chemistry</subject><subject>Cyclooxygenase 2 Inhibitors - pharmacology</subject><subject>Humans</subject><subject>Inflammation - drug therapy</subject><subject>Inflammation - enzymology</subject><subject>Inflammation - immunology</subject><subject>Molecular Docking Simulation</subject><subject>Oxazines</subject><subject>Oxazines - chemical synthesis</subject><subject>Oxazines - chemistry</subject><subject>Oxazines - pharmacology</subject><subject>Proinflammatory disease</subject><subject>SCS-Bi2O3</subject><issn>0960-894X</issn><issn>1464-3405</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kMFqGzEQhkVoSFy3L9BD0bGXdaX1WKuFXkpI0kCghySQm5C1I1tmV3IkOWTz9JHZtMfAMHP5_h_mI-QbZwvOuPi5W6wH0y9qxlcLVgaaEzLjIKBaAlt9IjPWClbJFh7PyeeUdoxxYABn5LwWDGTTwow83Y0-bzG5RLXvqNnqqE3G6F51dsHTYKkPz9jT8KJfnccJ63AIPuU4MXmrc1k40rRH46wzuu9HmnXcYKZmNH0IL-MGvU5I6y_k1Oo-4df3OycPV5f3F3-q27_XNxe_bysDDcsV6tYAN6sOLbaW16KxXcPlClFz04Ct9RIbW7PySi0AJJOFEt26taCtQLmckx9T7z6GpwOmrAaXDPa99hgOSXEhZTEil1DQekJNDClFtGof3aDjqDhTR9Vqp46q1VG1YmWgKaHv7_2H9YDd_8g_twX4NQFYvnx2GFUyDr3BzkU0WXXBfdT_BtjXktQ</recordid><startdate>20150801</startdate><enddate>20150801</enddate><creator>Srinivas, V.</creator><creator>Mohan, Chakrabhavi Dhananjaya</creator><creator>Baburajeev, C.P.</creator><creator>Rangappa, Shobith</creator><creator>Jagadish, Swamy</creator><creator>Fuchs, Julian E.</creator><creator>Sukhorukov, Alexey Yu</creator><creator>Chandra</creator><creator>Mason, Daniel J.</creator><creator>Sharath Kumar, Kothanahally Shivaramu</creator><creator>Madegowda, Mahendra</creator><creator>Bender, Andreas</creator><creator>Basappa</creator><creator>Rangappa, Kanchugarakoppal Subbegowda</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></search><sort><creationdate>20150801</creationdate><title>Synthesis and characterization of novel oxazines and demonstration that they specifically target cyclooxygenase 2</title><author>Srinivas, V. ; Mohan, Chakrabhavi Dhananjaya ; Baburajeev, C.P. ; Rangappa, Shobith ; Jagadish, Swamy ; Fuchs, Julian E. ; Sukhorukov, Alexey Yu ; Chandra ; Mason, Daniel J. ; Sharath Kumar, Kothanahally Shivaramu ; Madegowda, Mahendra ; Bender, Andreas ; Basappa ; Rangappa, Kanchugarakoppal Subbegowda</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c470t-ea9c41c5defe9f1267fd7185eea1c74f2a3e7f2026026448089f16db9f4af6e83</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Anti-Inflammatory Agents - chemical synthesis</topic><topic>Anti-Inflammatory Agents - chemistry</topic><topic>Anti-Inflammatory Agents - pharmacology</topic><topic>COX2</topic><topic>Cyclooxygenase 2 - chemistry</topic><topic>Cyclooxygenase 2 - immunology</topic><topic>Cyclooxygenase 2 Inhibitors - chemical synthesis</topic><topic>Cyclooxygenase 2 Inhibitors - chemistry</topic><topic>Cyclooxygenase 2 Inhibitors - pharmacology</topic><topic>Humans</topic><topic>Inflammation - drug therapy</topic><topic>Inflammation - enzymology</topic><topic>Inflammation - immunology</topic><topic>Molecular Docking Simulation</topic><topic>Oxazines</topic><topic>Oxazines - chemical synthesis</topic><topic>Oxazines - chemistry</topic><topic>Oxazines - pharmacology</topic><topic>Proinflammatory disease</topic><topic>SCS-Bi2O3</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Srinivas, V.</creatorcontrib><creatorcontrib>Mohan, Chakrabhavi Dhananjaya</creatorcontrib><creatorcontrib>Baburajeev, C.P.</creatorcontrib><creatorcontrib>Rangappa, Shobith</creatorcontrib><creatorcontrib>Jagadish, Swamy</creatorcontrib><creatorcontrib>Fuchs, Julian E.</creatorcontrib><creatorcontrib>Sukhorukov, Alexey Yu</creatorcontrib><creatorcontrib>Chandra</creatorcontrib><creatorcontrib>Mason, Daniel J.</creatorcontrib><creatorcontrib>Sharath Kumar, Kothanahally Shivaramu</creatorcontrib><creatorcontrib>Madegowda, Mahendra</creatorcontrib><creatorcontrib>Bender, Andreas</creatorcontrib><creatorcontrib>Basappa</creatorcontrib><creatorcontrib>Rangappa, Kanchugarakoppal Subbegowda</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><jtitle>Bioorganic & medicinal chemistry letters</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Srinivas, V.</au><au>Mohan, Chakrabhavi Dhananjaya</au><au>Baburajeev, C.P.</au><au>Rangappa, Shobith</au><au>Jagadish, Swamy</au><au>Fuchs, Julian E.</au><au>Sukhorukov, Alexey Yu</au><au>Chandra</au><au>Mason, Daniel J.</au><au>Sharath Kumar, Kothanahally Shivaramu</au><au>Madegowda, Mahendra</au><au>Bender, Andreas</au><au>Basappa</au><au>Rangappa, Kanchugarakoppal Subbegowda</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Synthesis and characterization of novel oxazines and demonstration that they specifically target cyclooxygenase 2</atitle><jtitle>Bioorganic & medicinal chemistry letters</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>2015-08-01</date><risdate>2015</risdate><volume>25</volume><issue>15</issue><spage>2931</spage><epage>2936</epage><pages>2931-2936</pages><issn>0960-894X</issn><eissn>1464-3405</eissn><abstract>[Display omitted]
In the present study, we used solution combustion synthesis-bismuth oxide (Bi2O3) as catalyst for the simple and efficient synthesis of 1,2-oxazine based derivatives of 6-fluoro-3-(piperidin-4-yl)benzo[d]isoxazoles, 1-arylpiperazine and carbazoles. (4aR,8aR)-4-(4-Methoxyphenyl)-3-((4-(4-methoxyphenyl)piperazin-1-yl)methyl)-4a,5,6,7,8,8a-hexahydro-4H-benzo[e][1,2]oxazine was found to be the most potent compound with a high degree of selectivity in inhibition towards COX2 (1.7μM) over COX1 (40.4μM) demonstrating the significance of 1,2-oxazine derivatives in developing COX2 specific inhibitors. Molecular docking analyses demonstrated that an isoleucine residue in the active site of COX1 is responsible for lower affinity to COX1 and increased potency towards COX2. Overall, our study reveals that the new 1,2-oxazine-based small molecules qualify as lead structures in developing COX2-specific inhibitors for anti-inflammatory therapy.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>26048794</pmid><doi>10.1016/j.bmcl.2015.05.047</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Bioorganic & medicinal chemistry letters, 2015-08, Vol.25 (15), p.2931-2936 |
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| subjects | Anti-Inflammatory Agents - chemical synthesis Anti-Inflammatory Agents - chemistry Anti-Inflammatory Agents - pharmacology COX2 Cyclooxygenase 2 - chemistry Cyclooxygenase 2 - immunology Cyclooxygenase 2 Inhibitors - chemical synthesis Cyclooxygenase 2 Inhibitors - chemistry Cyclooxygenase 2 Inhibitors - pharmacology Humans Inflammation - drug therapy Inflammation - enzymology Inflammation - immunology Molecular Docking Simulation Oxazines Oxazines - chemical synthesis Oxazines - chemistry Oxazines - pharmacology Proinflammatory disease SCS-Bi2O3 |
| title | Synthesis and characterization of novel oxazines and demonstration that they specifically target cyclooxygenase 2 |
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