Design, synthesis, and biological activity of diaryl ether inhibitors of Toxoplasma gondii enoyl reductase
Triclosan is a potent inhibitor of Toxoplasma gondii enoyl reductase (TgENR), which is an essential enzyme for parasite survival. In view of triclosan’s poor druggability, which limits its therapeutic use, a new set of B-ring modified analogs were designed to optimize its physico-chemical properties...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2013-04, Vol.23 (7), p.2035-2043 |
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| container_title | Bioorganic & medicinal chemistry letters |
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| creator | Cheng, Gang Muench, Stephen P. Zhou, Ying Afanador, Gustavo A. Mui, Ernest J. Fomovska, Alina Lai, Bo Shiun Prigge, Sean T. Woods, Stuart Roberts, Craig W. Hickman, Mark R. Lee, Patty J. Leed, Susan E. Auschwitz, Jennifer M. Rice, David W. McLeod, Rima |
| description | Triclosan is a potent inhibitor of Toxoplasma gondii enoyl reductase (TgENR), which is an essential enzyme for parasite survival. In view of triclosan’s poor druggability, which limits its therapeutic use, a new set of B-ring modified analogs were designed to optimize its physico-chemical properties. These derivatives were synthesized and evaluated by in vitro assay and TgENR enzyme assay. Some analogs display improved solubility, permeability and a comparable MIC50 value to that of triclosan. Modeling of these inhibitors revealed the same overall binding mode with the enzyme as triclosan, but the B-ring modifications have additional interactions with the strongly conserved Asn130. |
| doi_str_mv | 10.1016/j.bmcl.2013.02.019 |
| format | Article |
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In view of triclosan’s poor druggability, which limits its therapeutic use, a new set of B-ring modified analogs were designed to optimize its physico-chemical properties. These derivatives were synthesized and evaluated by in vitro assay and TgENR enzyme assay. Some analogs display improved solubility, permeability and a comparable MIC50 value to that of triclosan. Modeling of these inhibitors revealed the same overall binding mode with the enzyme as triclosan, but the B-ring modifications have additional interactions with the strongly conserved Asn130.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2013.02.019</identifier><identifier>PMID: 23453069</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>ADMET ; Dose-Response Relationship, Drug ; Drug Design ; Enoyl-(Acyl-Carrier-Protein) Reductase (NADH) - antagonists & inhibitors ; Enoyl-(Acyl-Carrier-Protein) Reductase (NADH) - metabolism ; Models, Molecular ; Molecular Structure ; Structure-Activity Relationship ; TgENR ; Toxoplasma ; Toxoplasma - enzymology ; Triclosan ; Triclosan - chemical synthesis ; Triclosan - chemistry ; Triclosan - pharmacology</subject><ispartof>Bioorganic & medicinal chemistry letters, 2013-04, Vol.23 (7), p.2035-2043</ispartof><rights>2013 Elsevier Ltd</rights><rights>Copyright © 2013 Elsevier Ltd. 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All rights reserved. 2013</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c455t-e9c4461e95fb6d75b64e8166d6da3894bc834ee06ac9f3a60da5780e1495357c3</citedby><cites>FETCH-LOGICAL-c455t-e9c4461e95fb6d75b64e8166d6da3894bc834ee06ac9f3a60da5780e1495357c3</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.2013.02.019$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>230,314,780,784,885,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23453069$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Cheng, Gang</creatorcontrib><creatorcontrib>Muench, Stephen P.</creatorcontrib><creatorcontrib>Zhou, Ying</creatorcontrib><creatorcontrib>Afanador, Gustavo A.</creatorcontrib><creatorcontrib>Mui, Ernest J.</creatorcontrib><creatorcontrib>Fomovska, Alina</creatorcontrib><creatorcontrib>Lai, Bo Shiun</creatorcontrib><creatorcontrib>Prigge, Sean T.</creatorcontrib><creatorcontrib>Woods, Stuart</creatorcontrib><creatorcontrib>Roberts, Craig W.</creatorcontrib><creatorcontrib>Hickman, Mark R.</creatorcontrib><creatorcontrib>Lee, Patty J.</creatorcontrib><creatorcontrib>Leed, Susan E.</creatorcontrib><creatorcontrib>Auschwitz, Jennifer M.</creatorcontrib><creatorcontrib>Rice, David W.</creatorcontrib><creatorcontrib>McLeod, Rima</creatorcontrib><title>Design, synthesis, and biological activity of diaryl ether inhibitors of Toxoplasma gondii enoyl reductase</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>Triclosan is a potent inhibitor of Toxoplasma gondii enoyl reductase (TgENR), which is an essential enzyme for parasite survival. 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Modeling of these inhibitors revealed the same overall binding mode with the enzyme as triclosan, but the B-ring modifications have additional interactions with the strongly conserved Asn130.</description><subject>ADMET</subject><subject>Dose-Response Relationship, Drug</subject><subject>Drug Design</subject><subject>Enoyl-(Acyl-Carrier-Protein) Reductase (NADH) - antagonists & inhibitors</subject><subject>Enoyl-(Acyl-Carrier-Protein) Reductase (NADH) - metabolism</subject><subject>Models, Molecular</subject><subject>Molecular Structure</subject><subject>Structure-Activity Relationship</subject><subject>TgENR</subject><subject>Toxoplasma</subject><subject>Toxoplasma - enzymology</subject><subject>Triclosan</subject><subject>Triclosan - chemical synthesis</subject><subject>Triclosan - chemistry</subject><subject>Triclosan - pharmacology</subject><issn>0960-894X</issn><issn>1464-3405</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kN2KFDEQhYMo7uzqC3gheYDtttL5mWkQQVZXhQVvVvAupJPqmRp6kiHpHXbe3gyji954VQV1zqmqj7E3AloBwrzbtsPOT20HQrbQtSD6Z2whlFGNVKCfswX0BppVr35esMtStgBCgVIv2UUnlZZg-gXbfsJC63jNyzHOm9qXa-5i4AOlKa3Ju4k7P9OB5iNPIw_k8nHiWKWZU9zQQHPK5TS6T49pP7myc3ydYiDiGFPVZgwPfnYFX7EXo5sKvv5dr9iP28_3N1-bu-9fvt18vGu80npusPdKGYG9HgcTlnowClfCmGCCk_WZwa-kQgTjfD9KZyA4vVwBCtVrqZdeXrEP59z9w7DD4DHO2U12n2lXj7fJkf13Emlj1-lgpek0KFMDunOAz6mUjOOTV4A9kbdbeyJvT-QtdLaSr6a3f299svxBXQXvzwKsvx8Isy2eMHoMlNHPNiT6X_4vyNOYPQ</recordid><startdate>20130401</startdate><enddate>20130401</enddate><creator>Cheng, Gang</creator><creator>Muench, Stephen P.</creator><creator>Zhou, Ying</creator><creator>Afanador, Gustavo A.</creator><creator>Mui, Ernest J.</creator><creator>Fomovska, Alina</creator><creator>Lai, Bo Shiun</creator><creator>Prigge, Sean T.</creator><creator>Woods, Stuart</creator><creator>Roberts, Craig W.</creator><creator>Hickman, Mark R.</creator><creator>Lee, Patty J.</creator><creator>Leed, Susan E.</creator><creator>Auschwitz, Jennifer M.</creator><creator>Rice, David W.</creator><creator>McLeod, Rima</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>5PM</scope></search><sort><creationdate>20130401</creationdate><title>Design, synthesis, and biological activity of diaryl ether inhibitors of Toxoplasma gondii enoyl reductase</title><author>Cheng, Gang ; 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| ispartof | Bioorganic & medicinal chemistry letters, 2013-04, Vol.23 (7), p.2035-2043 |
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| language | eng |
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| source | MEDLINE; Elsevier ScienceDirect Journals Complete |
| subjects | ADMET Dose-Response Relationship, Drug Drug Design Enoyl-(Acyl-Carrier-Protein) Reductase (NADH) - antagonists & inhibitors Enoyl-(Acyl-Carrier-Protein) Reductase (NADH) - metabolism Models, Molecular Molecular Structure Structure-Activity Relationship TgENR Toxoplasma Toxoplasma - enzymology Triclosan Triclosan - chemical synthesis Triclosan - chemistry Triclosan - pharmacology |
| title | Design, synthesis, and biological activity of diaryl ether inhibitors of Toxoplasma gondii enoyl reductase |
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