Synthesis and in Vitro Antiprotozoal Activity of Bisbenzofuran Cations
Forty three cationic bisbenzofurans were synthesized either by interaction of o-hydroxyaldehydes with α-halogenated ketones followed by intramolecular ring closure or by a copper- or palladium-mediated heteroannulation of substituted o-iodophenols with terminal acetylenes. In vitro antiprotozoal act...
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| Veröffentlicht in: | Journal of medicinal chemistry 2007-11, Vol.50 (23), p.5807-5823 |
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| container_title | Journal of medicinal chemistry |
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| creator | Bakunova, Svetlana M Bakunov, Stanislav A Wenzler, Tanja Barszcz, Todd Werbovetz, Karl A Brun, Reto Hall, James Edwin Tidwell, Richard R |
| description | Forty three cationic bisbenzofurans were synthesized either by interaction of o-hydroxyaldehydes with α-halogenated ketones followed by intramolecular ring closure or by a copper- or palladium-mediated heteroannulation of substituted o-iodophenols with terminal acetylenes. In vitro antiprotozoal activities of compounds 1 − 43 against Trypanosoma brucei rhodesiense, Plasmodium falciparum, and Leishmania donovani and cytotoxicity against mammalian cells were influenced by the position and the type of cationic substituents as well as the length of the carbon linker between aromatic moieties. One bisamidine displayed an antitrypanosomal efficacy comparable to that of pentamidine and melarsoprol. Twenty two compounds were more potent than pentamidine and seven dications were more effective than artemisinin against P. falciparum. Eight bisbenzofurans displayed activity against L. donovani superior to that of pentamidine. Overall, bisamidines connected by two-carbon linkers exhibited the highest efficacies against T. b. rhodesiense, P. falciparum, and L. donovani. |
| doi_str_mv | 10.1021/jm0708634 |
| format | Article |
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In vitro antiprotozoal activities of compounds 1 − 43 against Trypanosoma brucei rhodesiense, Plasmodium falciparum, and Leishmania donovani and cytotoxicity against mammalian cells were influenced by the position and the type of cationic substituents as well as the length of the carbon linker between aromatic moieties. One bisamidine displayed an antitrypanosomal efficacy comparable to that of pentamidine and melarsoprol. Twenty two compounds were more potent than pentamidine and seven dications were more effective than artemisinin against P. falciparum. Eight bisbenzofurans displayed activity against L. donovani superior to that of pentamidine. Overall, bisamidines connected by two-carbon linkers exhibited the highest efficacies against T. b. rhodesiense, P. falciparum, and L. donovani.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm0708634</identifier><identifier>PMID: 17948982</identifier><identifier>CODEN: JMCMAR</identifier><language>eng</language><publisher>Washington, DC: American Chemical Society</publisher><subject>Animals ; Antibiotics. Antiinfectious agents. Antiparasitic agents ; Antimalarials - chemical synthesis ; Antimalarials - pharmacology ; Antimalarials - toxicity ; Antiparasitic agents ; Benzofurans - chemical synthesis ; Benzofurans - pharmacology ; Benzofurans - toxicity ; Biological and medical sciences ; Cations ; Leishmania donovani - drug effects ; Medical sciences ; Pharmacology. Drug treatments ; Plasmodium falciparum - drug effects ; Rats ; Structure-Activity Relationship ; Trypanocidal Agents - chemical synthesis ; Trypanocidal Agents - pharmacology ; Trypanocidal Agents - toxicity ; Trypanosoma brucei rhodesiense - drug effects</subject><ispartof>Journal of medicinal chemistry, 2007-11, Vol.50 (23), p.5807-5823</ispartof><rights>Copyright © 2007 American Chemical Society</rights><rights>2008 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a447t-a59fb955d76668d334e163da7d9d4e24156f95c1f1848ab0c04aa6601b0f73063</citedby><cites>FETCH-LOGICAL-a447t-a59fb955d76668d334e163da7d9d4e24156f95c1f1848ab0c04aa6601b0f73063</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/jm0708634$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm0708634$$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=19376044$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/17948982$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Bakunova, Svetlana M</creatorcontrib><creatorcontrib>Bakunov, Stanislav A</creatorcontrib><creatorcontrib>Wenzler, Tanja</creatorcontrib><creatorcontrib>Barszcz, Todd</creatorcontrib><creatorcontrib>Werbovetz, Karl A</creatorcontrib><creatorcontrib>Brun, Reto</creatorcontrib><creatorcontrib>Hall, James Edwin</creatorcontrib><creatorcontrib>Tidwell, Richard R</creatorcontrib><title>Synthesis and in Vitro Antiprotozoal Activity of Bisbenzofuran Cations</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>Forty three cationic bisbenzofurans were synthesized either by interaction of o-hydroxyaldehydes with α-halogenated ketones followed by intramolecular ring closure or by a copper- or palladium-mediated heteroannulation of substituted o-iodophenols with terminal acetylenes. In vitro antiprotozoal activities of compounds 1 − 43 against Trypanosoma brucei rhodesiense, Plasmodium falciparum, and Leishmania donovani and cytotoxicity against mammalian cells were influenced by the position and the type of cationic substituents as well as the length of the carbon linker between aromatic moieties. One bisamidine displayed an antitrypanosomal efficacy comparable to that of pentamidine and melarsoprol. Twenty two compounds were more potent than pentamidine and seven dications were more effective than artemisinin against P. falciparum. Eight bisbenzofurans displayed activity against L. donovani superior to that of pentamidine. Overall, bisamidines connected by two-carbon linkers exhibited the highest efficacies against T. b. rhodesiense, P. falciparum, and L. donovani.</description><subject>Animals</subject><subject>Antibiotics. Antiinfectious agents. Antiparasitic agents</subject><subject>Antimalarials - chemical synthesis</subject><subject>Antimalarials - pharmacology</subject><subject>Antimalarials - toxicity</subject><subject>Antiparasitic agents</subject><subject>Benzofurans - chemical synthesis</subject><subject>Benzofurans - pharmacology</subject><subject>Benzofurans - toxicity</subject><subject>Biological and medical sciences</subject><subject>Cations</subject><subject>Leishmania donovani - drug effects</subject><subject>Medical sciences</subject><subject>Pharmacology. Drug treatments</subject><subject>Plasmodium falciparum - drug effects</subject><subject>Rats</subject><subject>Structure-Activity Relationship</subject><subject>Trypanocidal Agents - chemical synthesis</subject><subject>Trypanocidal Agents - pharmacology</subject><subject>Trypanocidal Agents - toxicity</subject><subject>Trypanosoma brucei rhodesiense - drug effects</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2007</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpt0MtOAjEUBuDGaATRhS9gZuPCxejpZdqZJaB4w0sCum06l8YiTElbjPD0DoHAxtVZnC9_zvkROsdwjYHgm8kMBKScsgPUxgmBmKXADlEbgJCYcEJb6MT7CQBQTOgxamGRsTRLSRsNRss6fFXe-EjVZWTq6NMEZ6NuHczc2WBXVk2jbhHMjwnLyOqoZ3xe1SurF07VUV8FY2t_io60mvrqbDs76GNwN-4_xMO3-8d-dxgrxkSIVZLpPEuSUnDO05JSVmFOSyXKrGQVYTjhOksKrHHKUpVDAUwpzgHnoAUFTjvoapNbOOu9q7ScOzNTbikxyHUXctdFYy82dr7IZ1W5l9vnG3C5BcoXaqqbfwrj9y6jggNbB8UbZ3yofnd75b4lF1Qkcvw-klnv9uWJDl7l8z5XFV5O7MLVTSX_HPgHOEeAiA</recordid><startdate>20071115</startdate><enddate>20071115</enddate><creator>Bakunova, Svetlana M</creator><creator>Bakunov, Stanislav A</creator><creator>Wenzler, Tanja</creator><creator>Barszcz, Todd</creator><creator>Werbovetz, Karl A</creator><creator>Brun, Reto</creator><creator>Hall, James Edwin</creator><creator>Tidwell, Richard R</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></search><sort><creationdate>20071115</creationdate><title>Synthesis and in Vitro Antiprotozoal Activity of Bisbenzofuran Cations</title><author>Bakunova, Svetlana M ; Bakunov, Stanislav A ; Wenzler, Tanja ; Barszcz, Todd ; Werbovetz, Karl A ; Brun, Reto ; Hall, James Edwin ; Tidwell, Richard R</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a447t-a59fb955d76668d334e163da7d9d4e24156f95c1f1848ab0c04aa6601b0f73063</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2007</creationdate><topic>Animals</topic><topic>Antibiotics. Antiinfectious agents. Antiparasitic agents</topic><topic>Antimalarials - chemical synthesis</topic><topic>Antimalarials - pharmacology</topic><topic>Antimalarials - toxicity</topic><topic>Antiparasitic agents</topic><topic>Benzofurans - chemical synthesis</topic><topic>Benzofurans - pharmacology</topic><topic>Benzofurans - toxicity</topic><topic>Biological and medical sciences</topic><topic>Cations</topic><topic>Leishmania donovani - drug effects</topic><topic>Medical sciences</topic><topic>Pharmacology. Drug treatments</topic><topic>Plasmodium falciparum - drug effects</topic><topic>Rats</topic><topic>Structure-Activity Relationship</topic><topic>Trypanocidal Agents - chemical synthesis</topic><topic>Trypanocidal Agents - pharmacology</topic><topic>Trypanocidal Agents - toxicity</topic><topic>Trypanosoma brucei rhodesiense - drug effects</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Bakunova, Svetlana M</creatorcontrib><creatorcontrib>Bakunov, Stanislav A</creatorcontrib><creatorcontrib>Wenzler, Tanja</creatorcontrib><creatorcontrib>Barszcz, Todd</creatorcontrib><creatorcontrib>Werbovetz, Karl A</creatorcontrib><creatorcontrib>Brun, Reto</creatorcontrib><creatorcontrib>Hall, James Edwin</creatorcontrib><creatorcontrib>Tidwell, Richard R</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><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Bakunova, Svetlana M</au><au>Bakunov, Stanislav A</au><au>Wenzler, Tanja</au><au>Barszcz, Todd</au><au>Werbovetz, Karl A</au><au>Brun, Reto</au><au>Hall, James Edwin</au><au>Tidwell, Richard R</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Synthesis and in Vitro Antiprotozoal Activity of Bisbenzofuran Cations</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2007-11-15</date><risdate>2007</risdate><volume>50</volume><issue>23</issue><spage>5807</spage><epage>5823</epage><pages>5807-5823</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><coden>JMCMAR</coden><abstract>Forty three cationic bisbenzofurans were synthesized either by interaction of o-hydroxyaldehydes with α-halogenated ketones followed by intramolecular ring closure or by a copper- or palladium-mediated heteroannulation of substituted o-iodophenols with terminal acetylenes. In vitro antiprotozoal activities of compounds 1 − 43 against Trypanosoma brucei rhodesiense, Plasmodium falciparum, and Leishmania donovani and cytotoxicity against mammalian cells were influenced by the position and the type of cationic substituents as well as the length of the carbon linker between aromatic moieties. One bisamidine displayed an antitrypanosomal efficacy comparable to that of pentamidine and melarsoprol. Twenty two compounds were more potent than pentamidine and seven dications were more effective than artemisinin against P. falciparum. Eight bisbenzofurans displayed activity against L. donovani superior to that of pentamidine. Overall, bisamidines connected by two-carbon linkers exhibited the highest efficacies against T. b. rhodesiense, P. falciparum, and L. donovani.</abstract><cop>Washington, DC</cop><pub>American Chemical Society</pub><pmid>17948982</pmid><doi>10.1021/jm0708634</doi><tpages>17</tpages></addata></record> |
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| subjects | Animals Antibiotics. Antiinfectious agents. Antiparasitic agents Antimalarials - chemical synthesis Antimalarials - pharmacology Antimalarials - toxicity Antiparasitic agents Benzofurans - chemical synthesis Benzofurans - pharmacology Benzofurans - toxicity Biological and medical sciences Cations Leishmania donovani - drug effects Medical sciences Pharmacology. Drug treatments Plasmodium falciparum - drug effects Rats Structure-Activity Relationship Trypanocidal Agents - chemical synthesis Trypanocidal Agents - pharmacology Trypanocidal Agents - toxicity Trypanosoma brucei rhodesiense - drug effects |
| title | Synthesis and in Vitro Antiprotozoal Activity of Bisbenzofuran Cations |
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