Discoveries and Syntheses of Highly Potent Antimalarial Troponoids
Novel derivatives of puberulic acid were synthesized and their antimalarial properties were evaluated in vitro against the Plasmodium falciparum K1 parasite strain, cytotoxicity against a human diploid embryonic cell line MRC-5, and in vivo efficacy using a Plasmodium berghei-infected mouse model. F...
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| Veröffentlicht in: | Chemical & pharmaceutical bulletin 2021/06/01, Vol.69(6), pp.564-572 |
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| container_title | Chemical & pharmaceutical bulletin |
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| creator | Saito, Ryo Sennari, Goh Nakajima, Asuka Kimishima, Aoi Iwatsuki, Masato Ishiyama, Aki Hokari, Rei Hirose, Tomoyasu Sunazuka, Toshiaki |
| description | Novel derivatives of puberulic acid were synthesized and their antimalarial properties were evaluated in vitro against the Plasmodium falciparum K1 parasite strain, cytotoxicity against a human diploid embryonic cell line MRC-5, and in vivo efficacy using a Plasmodium berghei-infected mouse model. From previous information that three hydroxy groups on the tropone framework were essential for antimalarial activity, we converted the carboxylic acid moiety into the corresponding esters, amides, and ketones. These derivatives showed antimalarial activity against chloroquine-resistant Plasmodium in vitro equivalent to puberulic acid. We identified that the pentane-3-yl ester, cyclohexyl ester, iso-butyl ketone, cyclohexyl methyl ketone all show an especially potent antiparasitic effect in vivo at an oral dose of 15 mg/kg without any apparent toxicity. These esters were more effective than the existing commonly used antimalarial drug, artesunate. |
| doi_str_mv | 10.1248/cpb.c21-00132 |
| format | Article |
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From previous information that three hydroxy groups on the tropone framework were essential for antimalarial activity, we converted the carboxylic acid moiety into the corresponding esters, amides, and ketones. These derivatives showed antimalarial activity against chloroquine-resistant Plasmodium in vitro equivalent to puberulic acid. We identified that the pentane-3-yl ester, cyclohexyl ester, iso-butyl ketone, cyclohexyl methyl ketone all show an especially potent antiparasitic effect in vivo at an oral dose of 15 mg/kg without any apparent toxicity. These esters were more effective than the existing commonly used antimalarial drug, artesunate.</description><identifier>ISSN: 0009-2363</identifier><identifier>EISSN: 1347-5223</identifier><identifier>DOI: 10.1248/cpb.c21-00132</identifier><language>eng</language><publisher>Tokyo: The Pharmaceutical Society of Japan</publisher><subject>Amides ; Antimalarial activity ; Antimalarial agents ; Antiparasitic agents ; Artesunate ; Biocompatibility ; Carboxylic acids ; Chloroquine ; Cytotoxicity ; Diploids ; Embryos ; Esters ; Ketones ; natural product ; Parasites ; Pentane ; Plasmodium falciparum ; puberulic acid ; structure–activity relationship ; Toxicity ; tropolone ; tropone ; viticolin</subject><ispartof>Chemical and Pharmaceutical Bulletin, 2021/06/01, Vol.69(6), pp.564-572</ispartof><rights>2021 The Pharmaceutical Society of Japan</rights><rights>Copyright Japan Science and Technology Agency 2021</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c679t-e2e9fe1a658c14cbc86ba5c83d7ea2d4d130a399e878689f8e16a1206fb16b023</citedby><cites>FETCH-LOGICAL-c679t-e2e9fe1a658c14cbc86ba5c83d7ea2d4d130a399e878689f8e16a1206fb16b023</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,1881,27922,27923</link.rule.ids></links><search><creatorcontrib>Saito, Ryo</creatorcontrib><creatorcontrib>Sennari, Goh</creatorcontrib><creatorcontrib>Nakajima, Asuka</creatorcontrib><creatorcontrib>Kimishima, Aoi</creatorcontrib><creatorcontrib>Iwatsuki, Masato</creatorcontrib><creatorcontrib>Ishiyama, Aki</creatorcontrib><creatorcontrib>Hokari, Rei</creatorcontrib><creatorcontrib>Hirose, Tomoyasu</creatorcontrib><creatorcontrib>Sunazuka, Toshiaki</creatorcontrib><creatorcontrib>aGraduate School of Infection Control Sciences</creatorcontrib><creatorcontrib>bOmura Satoshi Memorial Institute</creatorcontrib><creatorcontrib>Kitasato University</creatorcontrib><title>Discoveries and Syntheses of Highly Potent Antimalarial Troponoids</title><title>Chemical & pharmaceutical bulletin</title><addtitle>Chem. Pharm. Bull.</addtitle><description>Novel derivatives of puberulic acid were synthesized and their antimalarial properties were evaluated in vitro against the Plasmodium falciparum K1 parasite strain, cytotoxicity against a human diploid embryonic cell line MRC-5, and in vivo efficacy using a Plasmodium berghei-infected mouse model. From previous information that three hydroxy groups on the tropone framework were essential for antimalarial activity, we converted the carboxylic acid moiety into the corresponding esters, amides, and ketones. These derivatives showed antimalarial activity against chloroquine-resistant Plasmodium in vitro equivalent to puberulic acid. We identified that the pentane-3-yl ester, cyclohexyl ester, iso-butyl ketone, cyclohexyl methyl ketone all show an especially potent antiparasitic effect in vivo at an oral dose of 15 mg/kg without any apparent toxicity. These esters were more effective than the existing commonly used antimalarial drug, artesunate.</description><subject>Amides</subject><subject>Antimalarial activity</subject><subject>Antimalarial agents</subject><subject>Antiparasitic agents</subject><subject>Artesunate</subject><subject>Biocompatibility</subject><subject>Carboxylic acids</subject><subject>Chloroquine</subject><subject>Cytotoxicity</subject><subject>Diploids</subject><subject>Embryos</subject><subject>Esters</subject><subject>Ketones</subject><subject>natural product</subject><subject>Parasites</subject><subject>Pentane</subject><subject>Plasmodium falciparum</subject><subject>puberulic acid</subject><subject>structure–activity relationship</subject><subject>Toxicity</subject><subject>tropolone</subject><subject>tropone</subject><subject>viticolin</subject><issn>0009-2363</issn><issn>1347-5223</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><recordid>eNpdkM1PGzEQxa2KSgTKkftKvXBZGNu7XvtIQ_mQkKhUOFte7yxx5NipvUHKf18nQSBxmdHIv3lv_Ag5p3BJWSOv7Lq_tIzWAJSzb2RGedPVLWP8iMwAQNWMC35MTnJeArAWOj4jv25ctvENk8NcmTBUf7dhWmAuUxyre_e68NvqT5wwTNV1mNzKeJOc8dVziusYohvyD_J9ND7j2Xs_JS-3v5_n9_Xj093D_PqxtqJTU40M1YjUiFZa2tjeStGb1ko-dGjY0AyUg-FKoeykkGqUSIWhDMTYU9ED46fk4qC7TvHfBvOkV-V29N4EjJusWcuLkQTRFvTnF3QZNymU63ZUqzoGjSpUfaBsijknHPU6lQ-mraagd4nqkqguiep9ooW_O_ArHJw1PgbvAn5K29zZBa6cZrDfEQpEaVJDK5pSOsYl5ZQ2RWl-UFrmybzih69Jk7Me975CabErH_6frwuTNAb-HxbLluw</recordid><startdate>20210601</startdate><enddate>20210601</enddate><creator>Saito, Ryo</creator><creator>Sennari, Goh</creator><creator>Nakajima, Asuka</creator><creator>Kimishima, Aoi</creator><creator>Iwatsuki, Masato</creator><creator>Ishiyama, Aki</creator><creator>Hokari, Rei</creator><creator>Hirose, Tomoyasu</creator><creator>Sunazuka, Toshiaki</creator><general>The Pharmaceutical Society of Japan</general><general>Pharmaceutical Society of Japan</general><general>Japan Science and Technology Agency</general><scope>AAYXX</scope><scope>CITATION</scope><scope>7TK</scope><scope>7TM</scope><scope>7U9</scope><scope>H94</scope><scope>7X8</scope></search><sort><creationdate>20210601</creationdate><title>Discoveries and Syntheses of Highly Potent Antimalarial Troponoids</title><author>Saito, Ryo ; Sennari, Goh ; Nakajima, Asuka ; Kimishima, Aoi ; Iwatsuki, Masato ; Ishiyama, Aki ; Hokari, Rei ; Hirose, Tomoyasu ; Sunazuka, Toshiaki</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c679t-e2e9fe1a658c14cbc86ba5c83d7ea2d4d130a399e878689f8e16a1206fb16b023</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Amides</topic><topic>Antimalarial activity</topic><topic>Antimalarial agents</topic><topic>Antiparasitic agents</topic><topic>Artesunate</topic><topic>Biocompatibility</topic><topic>Carboxylic acids</topic><topic>Chloroquine</topic><topic>Cytotoxicity</topic><topic>Diploids</topic><topic>Embryos</topic><topic>Esters</topic><topic>Ketones</topic><topic>natural product</topic><topic>Parasites</topic><topic>Pentane</topic><topic>Plasmodium falciparum</topic><topic>puberulic acid</topic><topic>structure–activity relationship</topic><topic>Toxicity</topic><topic>tropolone</topic><topic>tropone</topic><topic>viticolin</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Saito, Ryo</creatorcontrib><creatorcontrib>Sennari, Goh</creatorcontrib><creatorcontrib>Nakajima, Asuka</creatorcontrib><creatorcontrib>Kimishima, Aoi</creatorcontrib><creatorcontrib>Iwatsuki, Masato</creatorcontrib><creatorcontrib>Ishiyama, Aki</creatorcontrib><creatorcontrib>Hokari, Rei</creatorcontrib><creatorcontrib>Hirose, Tomoyasu</creatorcontrib><creatorcontrib>Sunazuka, Toshiaki</creatorcontrib><creatorcontrib>aGraduate School of Infection Control Sciences</creatorcontrib><creatorcontrib>bOmura Satoshi Memorial Institute</creatorcontrib><creatorcontrib>Kitasato University</creatorcontrib><collection>CrossRef</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Chemical & pharmaceutical bulletin</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Saito, Ryo</au><au>Sennari, Goh</au><au>Nakajima, Asuka</au><au>Kimishima, Aoi</au><au>Iwatsuki, Masato</au><au>Ishiyama, Aki</au><au>Hokari, Rei</au><au>Hirose, Tomoyasu</au><au>Sunazuka, Toshiaki</au><aucorp>aGraduate School of Infection Control Sciences</aucorp><aucorp>bOmura Satoshi Memorial Institute</aucorp><aucorp>Kitasato University</aucorp><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Discoveries and Syntheses of Highly Potent Antimalarial Troponoids</atitle><jtitle>Chemical & pharmaceutical bulletin</jtitle><addtitle>Chem. Pharm. Bull.</addtitle><date>2021-06-01</date><risdate>2021</risdate><volume>69</volume><issue>6</issue><spage>564</spage><epage>572</epage><pages>564-572</pages><issn>0009-2363</issn><eissn>1347-5223</eissn><abstract>Novel derivatives of puberulic acid were synthesized and their antimalarial properties were evaluated in vitro against the Plasmodium falciparum K1 parasite strain, cytotoxicity against a human diploid embryonic cell line MRC-5, and in vivo efficacy using a Plasmodium berghei-infected mouse model. From previous information that three hydroxy groups on the tropone framework were essential for antimalarial activity, we converted the carboxylic acid moiety into the corresponding esters, amides, and ketones. These derivatives showed antimalarial activity against chloroquine-resistant Plasmodium in vitro equivalent to puberulic acid. We identified that the pentane-3-yl ester, cyclohexyl ester, iso-butyl ketone, cyclohexyl methyl ketone all show an especially potent antiparasitic effect in vivo at an oral dose of 15 mg/kg without any apparent toxicity. These esters were more effective than the existing commonly used antimalarial drug, artesunate.</abstract><cop>Tokyo</cop><pub>The Pharmaceutical Society of Japan</pub><doi>10.1248/cpb.c21-00132</doi><tpages>9</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Amides Antimalarial activity Antimalarial agents Antiparasitic agents Artesunate Biocompatibility Carboxylic acids Chloroquine Cytotoxicity Diploids Embryos Esters Ketones natural product Parasites Pentane Plasmodium falciparum puberulic acid structure–activity relationship Toxicity tropolone tropone viticolin |
| title | Discoveries and Syntheses of Highly Potent Antimalarial Troponoids |
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