Arteether, a new antimalarial drug: synthesis and antimalarial properties
Arteether (6) has been prepared from dihydroquinghaosu (3) by etherification with ethanol in the presence of Lewis acid and separated from its chromatographically slower moving alpha-dihydroqinghaosu ethyl ether (7). The absolute stereochemistry at C-12 has been determined by 1H NMR data (J11,12, NO...
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| Veröffentlicht in: | Journal of medicinal chemistry 1988-03, Vol.31 (3), p.645-650 |
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| container_title | Journal of medicinal chemistry |
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| creator | Brossi, A Venugopalan, B Dominguez Gerpe, L Yeh, H. J. C Flippen-Anderson, J. L Buchs, P Luo, X. D Milhous, W Peters, W |
| description | Arteether (6) has been prepared from dihydroquinghaosu (3) by etherification with ethanol in the presence of Lewis acid and separated from its chromatographically slower moving alpha-dihydroqinghaosu ethyl ether (7). The absolute stereochemistry at C-12 has been determined by 1H NMR data (J11,12, NOESY). Ethyl ethers 6 and 7 showed potent in vitro inhibition of Plasmodium falciparum, and both compounds were highly potent antimalarials in mice infected with a drug-sensitive strain of Plasmodium berghei. Crystalline arteether (6) and its oily epimer 7 were 2-3 times more potent schizontocides than quinghaosu (1), but deoxy compounds 8, 9, and 11 were 100-300 times less potent in vitro than their corresponding peroxy precursors. Pharmacological studies have shown arteether(6) to have antimalarial activity in animals comparable to artesunate (2) and artemether (4), both of which are fast-acting blood schizontocides in humans. Arteether (6) has now been chosen for a clinical evaluation in high-risk malaria patients. |
| doi_str_mv | 10.1021/jm00398a026 |
| format | Article |
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J. C ; Flippen-Anderson, J. L ; Buchs, P ; Luo, X. D ; Milhous, W ; Peters, W</creator><creatorcontrib>Brossi, A ; Venugopalan, B ; Dominguez Gerpe, L ; Yeh, H. J. C ; Flippen-Anderson, J. L ; Buchs, P ; Luo, X. D ; Milhous, W ; Peters, W</creatorcontrib><description>Arteether (6) has been prepared from dihydroquinghaosu (3) by etherification with ethanol in the presence of Lewis acid and separated from its chromatographically slower moving alpha-dihydroqinghaosu ethyl ether (7). The absolute stereochemistry at C-12 has been determined by 1H NMR data (J11,12, NOESY). Ethyl ethers 6 and 7 showed potent in vitro inhibition of Plasmodium falciparum, and both compounds were highly potent antimalarials in mice infected with a drug-sensitive strain of Plasmodium berghei. Crystalline arteether (6) and its oily epimer 7 were 2-3 times more potent schizontocides than quinghaosu (1), but deoxy compounds 8, 9, and 11 were 100-300 times less potent in vitro than their corresponding peroxy precursors. Pharmacological studies have shown arteether(6) to have antimalarial activity in animals comparable to artesunate (2) and artemether (4), both of which are fast-acting blood schizontocides in humans. Arteether (6) has now been chosen for a clinical evaluation in high-risk malaria patients.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm00398a026</identifier><identifier>PMID: 3279208</identifier><identifier>CODEN: JMCMAR</identifier><language>eng</language><publisher>Washington, DC: American Chemical Society</publisher><subject>Alicyclic compounds, terpenoids, prostaglandins, steroids ; Animals ; Antimalarials - chemical synthesis ; Artemisinins ; Chemistry ; Condensed matter: structure, mechanical and thermal properties ; Exact sciences and technology ; Heterocyclic compounds ; Magnetic Resonance Spectroscopy ; Malaria - drug therapy ; Mice ; Models, Molecular ; Organic chemistry ; Organic compounds ; Physics ; Plasmodium ; Plasmodium berghei ; Plasmodium falciparum - drug effects ; Preparations and properties ; Sesquiterpenes - chemical synthesis ; Sesquiterpenes - pharmacology ; Structure of solids and liquids; crystallography ; Structure of specific crystalline solids ; Terpenoids</subject><ispartof>Journal of medicinal chemistry, 1988-03, Vol.31 (3), p.645-650</ispartof><rights>1988 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a414t-90565edd970558c1301c400b39d78f774e88f05dd07351f5a4817fb28ae121993</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/jm00398a026$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm00398a026$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,777,781,2752,27057,27905,27906,56719,56769</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=7554946$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/3279208$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Brossi, A</creatorcontrib><creatorcontrib>Venugopalan, B</creatorcontrib><creatorcontrib>Dominguez Gerpe, L</creatorcontrib><creatorcontrib>Yeh, H. J. C</creatorcontrib><creatorcontrib>Flippen-Anderson, J. L</creatorcontrib><creatorcontrib>Buchs, P</creatorcontrib><creatorcontrib>Luo, X. D</creatorcontrib><creatorcontrib>Milhous, W</creatorcontrib><creatorcontrib>Peters, W</creatorcontrib><title>Arteether, a new antimalarial drug: synthesis and antimalarial properties</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>Arteether (6) has been prepared from dihydroquinghaosu (3) by etherification with ethanol in the presence of Lewis acid and separated from its chromatographically slower moving alpha-dihydroqinghaosu ethyl ether (7). The absolute stereochemistry at C-12 has been determined by 1H NMR data (J11,12, NOESY). Ethyl ethers 6 and 7 showed potent in vitro inhibition of Plasmodium falciparum, and both compounds were highly potent antimalarials in mice infected with a drug-sensitive strain of Plasmodium berghei. Crystalline arteether (6) and its oily epimer 7 were 2-3 times more potent schizontocides than quinghaosu (1), but deoxy compounds 8, 9, and 11 were 100-300 times less potent in vitro than their corresponding peroxy precursors. Pharmacological studies have shown arteether(6) to have antimalarial activity in animals comparable to artesunate (2) and artemether (4), both of which are fast-acting blood schizontocides in humans. Arteether (6) has now been chosen for a clinical evaluation in high-risk malaria patients.</description><subject>Alicyclic compounds, terpenoids, prostaglandins, steroids</subject><subject>Animals</subject><subject>Antimalarials - chemical synthesis</subject><subject>Artemisinins</subject><subject>Chemistry</subject><subject>Condensed matter: structure, mechanical and thermal properties</subject><subject>Exact sciences and technology</subject><subject>Heterocyclic compounds</subject><subject>Magnetic Resonance Spectroscopy</subject><subject>Malaria - drug therapy</subject><subject>Mice</subject><subject>Models, Molecular</subject><subject>Organic chemistry</subject><subject>Organic compounds</subject><subject>Physics</subject><subject>Plasmodium</subject><subject>Plasmodium berghei</subject><subject>Plasmodium falciparum - drug effects</subject><subject>Preparations and properties</subject><subject>Sesquiterpenes - chemical synthesis</subject><subject>Sesquiterpenes - pharmacology</subject><subject>Structure of solids and liquids; crystallography</subject><subject>Structure of specific crystalline solids</subject><subject>Terpenoids</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1988</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqF0M9PwjAcBfDGaBDRk2eTHYwedPrtr7XzhihKgkoCxmNTtk6HY2C7RfnvLYEQTUw89fA-eW0fQocYLjAQfDmZAtBYaiDRFmpiTiBkEtg2agIQEpKI0F2059wEvMOENlCDEhETkE3Ua9vKmOrN2PNAB6X5DHRZ5VNdaJvrIkht_XoVuEXphcudD9PfYG5nc2Or3Lh9tJPpwpmD9dlCz93bUec-7D_d9TrtfqgZZlUYA4-4SdNYAOcywRRwwgDGNE6FzIRgRsoMeJqCoBxnXDOJRTYmUhtMcBzTFjpZ9fqrP2rjKjXNXWKKQpdmVjslpP8ij-i_EHNKQYhl49kKJnbmnDWZmlv_Q7tQGNRyYfVjYa-P1rX1eGrSjV1P6vPjda5doovM6jLJ3YYJzlnMljXhiuWuMl-bWNt3FQkquBoNhur65eZx8NAdqoH3pyuvE6cms9qWfuQ_H_gNSJ-dAg</recordid><startdate>19880301</startdate><enddate>19880301</enddate><creator>Brossi, A</creator><creator>Venugopalan, B</creator><creator>Dominguez Gerpe, L</creator><creator>Yeh, H. J. C</creator><creator>Flippen-Anderson, J. L</creator><creator>Buchs, P</creator><creator>Luo, X. D</creator><creator>Milhous, W</creator><creator>Peters, W</creator><general>American Chemical Society</general><scope>BSCLL</scope><scope>IQODW</scope><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>M7N</scope><scope>7X8</scope></search><sort><creationdate>19880301</creationdate><title>Arteether, a new antimalarial drug: synthesis and antimalarial properties</title><author>Brossi, A ; Venugopalan, B ; Dominguez Gerpe, L ; Yeh, H. J. C ; Flippen-Anderson, J. L ; Buchs, P ; Luo, X. D ; Milhous, W ; Peters, W</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a414t-90565edd970558c1301c400b39d78f774e88f05dd07351f5a4817fb28ae121993</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1988</creationdate><topic>Alicyclic compounds, terpenoids, prostaglandins, steroids</topic><topic>Animals</topic><topic>Antimalarials - chemical synthesis</topic><topic>Artemisinins</topic><topic>Chemistry</topic><topic>Condensed matter: structure, mechanical and thermal properties</topic><topic>Exact sciences and technology</topic><topic>Heterocyclic compounds</topic><topic>Magnetic Resonance Spectroscopy</topic><topic>Malaria - drug therapy</topic><topic>Mice</topic><topic>Models, Molecular</topic><topic>Organic chemistry</topic><topic>Organic compounds</topic><topic>Physics</topic><topic>Plasmodium</topic><topic>Plasmodium berghei</topic><topic>Plasmodium falciparum - drug effects</topic><topic>Preparations and properties</topic><topic>Sesquiterpenes - chemical synthesis</topic><topic>Sesquiterpenes - pharmacology</topic><topic>Structure of solids and liquids; crystallography</topic><topic>Structure of specific crystalline solids</topic><topic>Terpenoids</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Brossi, A</creatorcontrib><creatorcontrib>Venugopalan, B</creatorcontrib><creatorcontrib>Dominguez Gerpe, L</creatorcontrib><creatorcontrib>Yeh, H. J. C</creatorcontrib><creatorcontrib>Flippen-Anderson, J. L</creatorcontrib><creatorcontrib>Buchs, P</creatorcontrib><creatorcontrib>Luo, X. D</creatorcontrib><creatorcontrib>Milhous, W</creatorcontrib><creatorcontrib>Peters, W</creatorcontrib><collection>Istex</collection><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Brossi, A</au><au>Venugopalan, B</au><au>Dominguez Gerpe, L</au><au>Yeh, H. J. C</au><au>Flippen-Anderson, J. L</au><au>Buchs, P</au><au>Luo, X. D</au><au>Milhous, W</au><au>Peters, W</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Arteether, a new antimalarial drug: synthesis and antimalarial properties</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>1988-03-01</date><risdate>1988</risdate><volume>31</volume><issue>3</issue><spage>645</spage><epage>650</epage><pages>645-650</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><coden>JMCMAR</coden><abstract>Arteether (6) has been prepared from dihydroquinghaosu (3) by etherification with ethanol in the presence of Lewis acid and separated from its chromatographically slower moving alpha-dihydroqinghaosu ethyl ether (7). The absolute stereochemistry at C-12 has been determined by 1H NMR data (J11,12, NOESY). Ethyl ethers 6 and 7 showed potent in vitro inhibition of Plasmodium falciparum, and both compounds were highly potent antimalarials in mice infected with a drug-sensitive strain of Plasmodium berghei. Crystalline arteether (6) and its oily epimer 7 were 2-3 times more potent schizontocides than quinghaosu (1), but deoxy compounds 8, 9, and 11 were 100-300 times less potent in vitro than their corresponding peroxy precursors. Pharmacological studies have shown arteether(6) to have antimalarial activity in animals comparable to artesunate (2) and artemether (4), both of which are fast-acting blood schizontocides in humans. Arteether (6) has now been chosen for a clinical evaluation in high-risk malaria patients.</abstract><cop>Washington, DC</cop><pub>American Chemical Society</pub><pmid>3279208</pmid><doi>10.1021/jm00398a026</doi><tpages>6</tpages></addata></record> |
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| ispartof | Journal of medicinal chemistry, 1988-03, Vol.31 (3), p.645-650 |
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| subjects | Alicyclic compounds, terpenoids, prostaglandins, steroids Animals Antimalarials - chemical synthesis Artemisinins Chemistry Condensed matter: structure, mechanical and thermal properties Exact sciences and technology Heterocyclic compounds Magnetic Resonance Spectroscopy Malaria - drug therapy Mice Models, Molecular Organic chemistry Organic compounds Physics Plasmodium Plasmodium berghei Plasmodium falciparum - drug effects Preparations and properties Sesquiterpenes - chemical synthesis Sesquiterpenes - pharmacology Structure of solids and liquids crystallography Structure of specific crystalline solids Terpenoids |
| title | Arteether, a new antimalarial drug: synthesis and antimalarial properties |
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