Design, synthesis, and biological evaluation of 5‐(4‐(pyridin‐4‐yl)‐1H‐1,2,3‐triazol‐1‐yl)benzonitrile derivatives as xanthine oxidase inhibitors
A series of 5‐(4‐(pyridin‐4‐yl)‐1H‐1,2,3‐triazol‐1‐yl)benzonitrile derivatives (1a–p) was designed, synthesized, and identified as xanthine oxidase inhibitors with micromolar level potencies. Among them, the most promising compounds 1j and 1k were obtained with IC50 values of 8.1 and 6.7 μm, respect...
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| Veröffentlicht in: | Chemical biology & drug design 2018-02, Vol.91 (2), p.526-533 |
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| creator | Zhang, Ting‐jian Li, Song‐ye Zhang, Yi Wu, Qing‐xia Meng, Fan‐hao |
| description | A series of 5‐(4‐(pyridin‐4‐yl)‐1H‐1,2,3‐triazol‐1‐yl)benzonitrile derivatives (1a–p) was designed, synthesized, and identified as xanthine oxidase inhibitors with micromolar level potencies. Among them, the most promising compounds 1j and 1k were obtained with IC50 values of 8.1 and 6.7 μm, respectively. The Lineweaver–Burk plot revealed that compound 1k acted as a mixed‐type xanthine oxidase inhibitor. SAR analysis revealed that a carbon atom occupying the X3 position is not as effective as a nitrogen atom, and an iso‐pentyloxy or a cyclopentyloxy at the 2‐position of benzonitrile moiety will benefit the inhibitory potency. The basis of xanthine oxidase inhibition by 1k was rationalized by molecular modeling studies.
The title compounds were designed, synthesized, and identified as XO inhibitors. SAR analysis revealed that a carbon atom occupying the X3 position is not as effective as a nitrogen atom, and an iso‐pentyloxy or a cyclopentyloxy at the 2‐position of benzonitrile moiety will benefit the inhibitory potency. The Lineweaver–Burk plot revealed that compound lk acted as a mixed‐type xanthine oxidase inhibitor and the molecular modeling studies rationalized the basis of XO inhibition by lk. |
| doi_str_mv | 10.1111/cbdd.13114 |
| format | Article |
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The title compounds were designed, synthesized, and identified as XO inhibitors. SAR analysis revealed that a carbon atom occupying the X3 position is not as effective as a nitrogen atom, and an iso‐pentyloxy or a cyclopentyloxy at the 2‐position of benzonitrile moiety will benefit the inhibitory potency. The Lineweaver–Burk plot revealed that compound lk acted as a mixed‐type xanthine oxidase inhibitor and the molecular modeling studies rationalized the basis of XO inhibition by lk.</description><identifier>ISSN: 1747-0277</identifier><identifier>EISSN: 1747-0285</identifier><identifier>DOI: 10.1111/cbdd.13114</identifier><identifier>PMID: 28950055</identifier><language>eng</language><publisher>England</publisher><subject>1,2,3‐triazole ; Animals ; Binding Sites ; Catalytic Domain ; Cattle ; Drug Design ; Enzyme Inhibitors - chemical synthesis ; Enzyme Inhibitors - metabolism ; Inhibitory Concentration 50 ; Kinetics ; Molecular Docking Simulation ; Nitriles - chemistry ; Nitriles - metabolism ; Structure-Activity Relationship ; topiroxostat ; Xanthine Oxidase - antagonists & inhibitors ; Xanthine Oxidase - metabolism ; xanthine oxidase inhibitor</subject><ispartof>Chemical biology & drug design, 2018-02, Vol.91 (2), p.526-533</ispartof><rights>2017 John Wiley & Sons A/S</rights><rights>2017 John Wiley & Sons A/S.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><orcidid>0000-0002-1331-2164</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1111%2Fcbdd.13114$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1111%2Fcbdd.13114$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,780,784,1416,27915,27916,45565,45566</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28950055$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Zhang, Ting‐jian</creatorcontrib><creatorcontrib>Li, Song‐ye</creatorcontrib><creatorcontrib>Zhang, Yi</creatorcontrib><creatorcontrib>Wu, Qing‐xia</creatorcontrib><creatorcontrib>Meng, Fan‐hao</creatorcontrib><title>Design, synthesis, and biological evaluation of 5‐(4‐(pyridin‐4‐yl)‐1H‐1,2,3‐triazol‐1‐yl)benzonitrile derivatives as xanthine oxidase inhibitors</title><title>Chemical biology & drug design</title><addtitle>Chem Biol Drug Des</addtitle><description>A series of 5‐(4‐(pyridin‐4‐yl)‐1H‐1,2,3‐triazol‐1‐yl)benzonitrile derivatives (1a–p) was designed, synthesized, and identified as xanthine oxidase inhibitors with micromolar level potencies. Among them, the most promising compounds 1j and 1k were obtained with IC50 values of 8.1 and 6.7 μm, respectively. The Lineweaver–Burk plot revealed that compound 1k acted as a mixed‐type xanthine oxidase inhibitor. SAR analysis revealed that a carbon atom occupying the X3 position is not as effective as a nitrogen atom, and an iso‐pentyloxy or a cyclopentyloxy at the 2‐position of benzonitrile moiety will benefit the inhibitory potency. The basis of xanthine oxidase inhibition by 1k was rationalized by molecular modeling studies.
The title compounds were designed, synthesized, and identified as XO inhibitors. SAR analysis revealed that a carbon atom occupying the X3 position is not as effective as a nitrogen atom, and an iso‐pentyloxy or a cyclopentyloxy at the 2‐position of benzonitrile moiety will benefit the inhibitory potency. The Lineweaver–Burk plot revealed that compound lk acted as a mixed‐type xanthine oxidase inhibitor and the molecular modeling studies rationalized the basis of XO inhibition by lk.</description><subject>1,2,3‐triazole</subject><subject>Animals</subject><subject>Binding Sites</subject><subject>Catalytic Domain</subject><subject>Cattle</subject><subject>Drug Design</subject><subject>Enzyme Inhibitors - chemical synthesis</subject><subject>Enzyme Inhibitors - metabolism</subject><subject>Inhibitory Concentration 50</subject><subject>Kinetics</subject><subject>Molecular Docking Simulation</subject><subject>Nitriles - chemistry</subject><subject>Nitriles - metabolism</subject><subject>Structure-Activity Relationship</subject><subject>topiroxostat</subject><subject>Xanthine Oxidase - antagonists & inhibitors</subject><subject>Xanthine Oxidase - metabolism</subject><subject>xanthine oxidase inhibitor</subject><issn>1747-0277</issn><issn>1747-0285</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo9UUtOIzEQtdAgEpjZcICRl4yUgL_9WQ4JPykSm5l1y25XEyPHzrQ7GZoVR-AO3IyT4CaAF69elZ-qVPUQOqbklKZ3VmtjTimnVOyhMc1FPiWskN--eJ6P0GGM94QIIVlxgEasKCUhUo7RyxyivfMTHHvfLROPE6y8wdoGF-5srRyGrXIb1dngcWiwfH16PhEDrPvWGusTHdLe_UpIrweYsAlPsWutegxuqOwEGvxj8DbVHWADrd2mtluIWEX8oNJ86wGHB2tUBGz90mrbhTZ-R_uNchF-fMQj9Pfy4s_serq4vbqZ_V5M10xyMc2k1ECJzg1p0tJGFRoyqFnRMEWE0TlRuRa1gFKWHFhmVGmKjLMGpKwbmfMjdLLru27Dvw3ErlrZWINzykPYxIqWgmei4Iwk6c8P6UavwFTr1q5U21efh00CuhP8T7v2X_-UVINl1WBZ9W5ZNTufz98ZfwN7_JN0</recordid><startdate>201802</startdate><enddate>201802</enddate><creator>Zhang, Ting‐jian</creator><creator>Li, Song‐ye</creator><creator>Zhang, Yi</creator><creator>Wu, Qing‐xia</creator><creator>Meng, Fan‐hao</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0002-1331-2164</orcidid></search><sort><creationdate>201802</creationdate><title>Design, synthesis, and biological evaluation of 5‐(4‐(pyridin‐4‐yl)‐1H‐1,2,3‐triazol‐1‐yl)benzonitrile derivatives as xanthine oxidase inhibitors</title><author>Zhang, Ting‐jian ; Li, Song‐ye ; Zhang, Yi ; Wu, Qing‐xia ; Meng, Fan‐hao</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-p2534-655be10b7d0f027da8be6ec28f2a04db70a7b4c4e9593e26da9d8632fe55cf573</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>1,2,3‐triazole</topic><topic>Animals</topic><topic>Binding Sites</topic><topic>Catalytic Domain</topic><topic>Cattle</topic><topic>Drug Design</topic><topic>Enzyme Inhibitors - chemical synthesis</topic><topic>Enzyme Inhibitors - metabolism</topic><topic>Inhibitory Concentration 50</topic><topic>Kinetics</topic><topic>Molecular Docking Simulation</topic><topic>Nitriles - chemistry</topic><topic>Nitriles - metabolism</topic><topic>Structure-Activity Relationship</topic><topic>topiroxostat</topic><topic>Xanthine Oxidase - antagonists & inhibitors</topic><topic>Xanthine Oxidase - metabolism</topic><topic>xanthine oxidase inhibitor</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Zhang, Ting‐jian</creatorcontrib><creatorcontrib>Li, Song‐ye</creatorcontrib><creatorcontrib>Zhang, Yi</creatorcontrib><creatorcontrib>Wu, Qing‐xia</creatorcontrib><creatorcontrib>Meng, Fan‐hao</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>MEDLINE - Academic</collection><jtitle>Chemical biology & drug design</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Zhang, Ting‐jian</au><au>Li, Song‐ye</au><au>Zhang, Yi</au><au>Wu, Qing‐xia</au><au>Meng, Fan‐hao</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Design, synthesis, and biological evaluation of 5‐(4‐(pyridin‐4‐yl)‐1H‐1,2,3‐triazol‐1‐yl)benzonitrile derivatives as xanthine oxidase inhibitors</atitle><jtitle>Chemical biology & drug design</jtitle><addtitle>Chem Biol Drug Des</addtitle><date>2018-02</date><risdate>2018</risdate><volume>91</volume><issue>2</issue><spage>526</spage><epage>533</epage><pages>526-533</pages><issn>1747-0277</issn><eissn>1747-0285</eissn><abstract>A series of 5‐(4‐(pyridin‐4‐yl)‐1H‐1,2,3‐triazol‐1‐yl)benzonitrile derivatives (1a–p) was designed, synthesized, and identified as xanthine oxidase inhibitors with micromolar level potencies. Among them, the most promising compounds 1j and 1k were obtained with IC50 values of 8.1 and 6.7 μm, respectively. The Lineweaver–Burk plot revealed that compound 1k acted as a mixed‐type xanthine oxidase inhibitor. SAR analysis revealed that a carbon atom occupying the X3 position is not as effective as a nitrogen atom, and an iso‐pentyloxy or a cyclopentyloxy at the 2‐position of benzonitrile moiety will benefit the inhibitory potency. The basis of xanthine oxidase inhibition by 1k was rationalized by molecular modeling studies.
The title compounds were designed, synthesized, and identified as XO inhibitors. SAR analysis revealed that a carbon atom occupying the X3 position is not as effective as a nitrogen atom, and an iso‐pentyloxy or a cyclopentyloxy at the 2‐position of benzonitrile moiety will benefit the inhibitory potency. The Lineweaver–Burk plot revealed that compound lk acted as a mixed‐type xanthine oxidase inhibitor and the molecular modeling studies rationalized the basis of XO inhibition by lk.</abstract><cop>England</cop><pmid>28950055</pmid><doi>10.1111/cbdd.13114</doi><tpages>8</tpages><orcidid>https://orcid.org/0000-0002-1331-2164</orcidid></addata></record> |
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| subjects | 1,2,3‐triazole Animals Binding Sites Catalytic Domain Cattle Drug Design Enzyme Inhibitors - chemical synthesis Enzyme Inhibitors - metabolism Inhibitory Concentration 50 Kinetics Molecular Docking Simulation Nitriles - chemistry Nitriles - metabolism Structure-Activity Relationship topiroxostat Xanthine Oxidase - antagonists & inhibitors Xanthine Oxidase - metabolism xanthine oxidase inhibitor |
| title | Design, synthesis, and biological evaluation of 5‐(4‐(pyridin‐4‐yl)‐1H‐1,2,3‐triazol‐1‐yl)benzonitrile derivatives as xanthine oxidase inhibitors |
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