Combining 4-Aminoquinoline- and Clotrimazole-Based Pharmacophores toward Innovative and Potent Hybrid Antimalarials
Antimalarial agents structurally based on novel pharmacophores, synthesized by low-cost synthetic procedures and characterized by low potential for developing resistance are urgently needed. Recently, we developed an innovative class of antimalarials based on a polyaromatic pharmacophore. Hybridizin...
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| Veröffentlicht in: | Journal of medicinal chemistry 2009-01, Vol.52 (2), p.502-513 |
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| creator | Gemma, Sandra Campiani, Giuseppe Butini, Stefania Joshi, Bhupendra P Kukreja, Gagan Coccone, Salvatore Sanna Bernetti, Matteo Persico, Marco Nacci, Vito Fiorini, Isabella Novellino, Ettore Taramelli, Donatella Basilico, Nicoletta Parapini, Silvia Yardley, Vanessa Croft, Simon Keller-Maerki, Sonja Rottmann, Matthias Brun, Reto Coletta, Massimiliano Marini, Stefano Guiso, Giovanna Caccia, Silvio Fattorusso, Caterina |
| description | Antimalarial agents structurally based on novel pharmacophores, synthesized by low-cost synthetic procedures and characterized by low potential for developing resistance are urgently needed. Recently, we developed an innovative class of antimalarials based on a polyaromatic pharmacophore. Hybridizing the 4-aminoquinoline or the 9-aminoacridine system of known antimalarials with the clotrimazole-like pharmacophore, characterized by a polyarylmethyl group, we describe herein the development of a unique class (4a−l and 5a−c) of antimalarials selectively interacting with free heme and interfering with Plasmodium falciparum (Pf) heme metabolism. Combination of the polyarylmethyl system, able to form and stabilize radical intermediates, with the iron-complexing and conjugation-mediated electron transfer properties of the 4(9)-aminoquinoline(acridine) system led to potent antimalarials in vitro against chloroquine sensitive and resistant Pf strains. Among the compounds synthesized, 4g was active in vivo against P. chabaudi and P. berghei after oral administration and, possessing promising pharmacokinetic properties, it is a candidate for further preclinical development. |
| doi_str_mv | 10.1021/jm801352s |
| format | Article |
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Recently, we developed an innovative class of antimalarials based on a polyaromatic pharmacophore. Hybridizing the 4-aminoquinoline or the 9-aminoacridine system of known antimalarials with the clotrimazole-like pharmacophore, characterized by a polyarylmethyl group, we describe herein the development of a unique class (4a−l and 5a−c) of antimalarials selectively interacting with free heme and interfering with Plasmodium falciparum (Pf) heme metabolism. Combination of the polyarylmethyl system, able to form and stabilize radical intermediates, with the iron-complexing and conjugation-mediated electron transfer properties of the 4(9)-aminoquinoline(acridine) system led to potent antimalarials in vitro against chloroquine sensitive and resistant Pf strains. Among the compounds synthesized, 4g was active in vivo against P. chabaudi and P. berghei after oral administration and, possessing promising pharmacokinetic properties, it is a candidate for further preclinical development.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm801352s</identifier><identifier>PMID: 19113955</identifier><identifier>CODEN: JMCMAR</identifier><language>eng</language><publisher>Columbus, OH: American Chemical Society</publisher><subject>Aminoquinolines - chemistry ; Aminoquinolines - pharmacokinetics ; Aminoquinolines - pharmacology ; Animals ; Antibiotics. Antiinfectious agents. Antiparasitic agents ; Antimalarials - chemical synthesis ; Antimalarials - pharmacokinetics ; Antimalarials - pharmacology ; Antiparasitic agents ; Biological and medical sciences ; Cell Line ; Clotrimazole - chemistry ; Clotrimazole - pharmacokinetics ; Clotrimazole - pharmacology ; Humans ; Magnetic Resonance Spectroscopy ; Medical sciences ; Mice ; Pharmacology. Drug treatments ; Plasmodium - drug effects ; Rats ; Species Specificity ; Spectrometry, Mass, Electrospray Ionization</subject><ispartof>Journal of medicinal chemistry, 2009-01, Vol.52 (2), p.502-513</ispartof><rights>Copyright © 2009 American Chemical Society</rights><rights>2009 INIST-CNRS</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a378t-a5185c05cf1bf33f11a662fa0664889f8e8638f9e6c643f209f7691f95786a5d3</citedby><cites>FETCH-LOGICAL-a378t-a5185c05cf1bf33f11a662fa0664889f8e8638f9e6c643f209f7691f95786a5d3</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/jm801352s$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm801352s$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>315,782,786,2769,27085,27933,27934,56747,56797</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=21066279$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/19113955$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Gemma, Sandra</creatorcontrib><creatorcontrib>Campiani, Giuseppe</creatorcontrib><creatorcontrib>Butini, Stefania</creatorcontrib><creatorcontrib>Joshi, Bhupendra P</creatorcontrib><creatorcontrib>Kukreja, Gagan</creatorcontrib><creatorcontrib>Coccone, Salvatore Sanna</creatorcontrib><creatorcontrib>Bernetti, Matteo</creatorcontrib><creatorcontrib>Persico, Marco</creatorcontrib><creatorcontrib>Nacci, Vito</creatorcontrib><creatorcontrib>Fiorini, Isabella</creatorcontrib><creatorcontrib>Novellino, Ettore</creatorcontrib><creatorcontrib>Taramelli, Donatella</creatorcontrib><creatorcontrib>Basilico, Nicoletta</creatorcontrib><creatorcontrib>Parapini, Silvia</creatorcontrib><creatorcontrib>Yardley, Vanessa</creatorcontrib><creatorcontrib>Croft, Simon</creatorcontrib><creatorcontrib>Keller-Maerki, Sonja</creatorcontrib><creatorcontrib>Rottmann, Matthias</creatorcontrib><creatorcontrib>Brun, Reto</creatorcontrib><creatorcontrib>Coletta, Massimiliano</creatorcontrib><creatorcontrib>Marini, Stefano</creatorcontrib><creatorcontrib>Guiso, Giovanna</creatorcontrib><creatorcontrib>Caccia, Silvio</creatorcontrib><creatorcontrib>Fattorusso, Caterina</creatorcontrib><title>Combining 4-Aminoquinoline- and Clotrimazole-Based Pharmacophores toward Innovative and Potent Hybrid Antimalarials</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>Antimalarial agents structurally based on novel pharmacophores, synthesized by low-cost synthetic procedures and characterized by low potential for developing resistance are urgently needed. Recently, we developed an innovative class of antimalarials based on a polyaromatic pharmacophore. Hybridizing the 4-aminoquinoline or the 9-aminoacridine system of known antimalarials with the clotrimazole-like pharmacophore, characterized by a polyarylmethyl group, we describe herein the development of a unique class (4a−l and 5a−c) of antimalarials selectively interacting with free heme and interfering with Plasmodium falciparum (Pf) heme metabolism. Combination of the polyarylmethyl system, able to form and stabilize radical intermediates, with the iron-complexing and conjugation-mediated electron transfer properties of the 4(9)-aminoquinoline(acridine) system led to potent antimalarials in vitro against chloroquine sensitive and resistant Pf strains. Among the compounds synthesized, 4g was active in vivo against P. chabaudi and P. berghei after oral administration and, possessing promising pharmacokinetic properties, it is a candidate for further preclinical development.</description><subject>Aminoquinolines - chemistry</subject><subject>Aminoquinolines - pharmacokinetics</subject><subject>Aminoquinolines - pharmacology</subject><subject>Animals</subject><subject>Antibiotics. Antiinfectious agents. Antiparasitic agents</subject><subject>Antimalarials - chemical synthesis</subject><subject>Antimalarials - pharmacokinetics</subject><subject>Antimalarials - pharmacology</subject><subject>Antiparasitic agents</subject><subject>Biological and medical sciences</subject><subject>Cell Line</subject><subject>Clotrimazole - chemistry</subject><subject>Clotrimazole - pharmacokinetics</subject><subject>Clotrimazole - pharmacology</subject><subject>Humans</subject><subject>Magnetic Resonance Spectroscopy</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Pharmacology. Drug treatments</subject><subject>Plasmodium - drug effects</subject><subject>Rats</subject><subject>Species Specificity</subject><subject>Spectrometry, Mass, Electrospray Ionization</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2009</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNptkLFO5DAQhi0Egr2FghdAaUC6IuCxY8cplxUHSEhQQB3NOjZ4ldiLnQXB02OOFTQ0M803_8x8hBwCPQXK4Gw5KApcsLRFJiAYLStFq20yoZSxkknG98iflJaUUg6M75I9aAB4I8SEpHkYFs47_1hU5WxwPjyvc-mdN2WBvivmfRijG_A99KY8x2S64u4J44A6rJ5CNKkYwyvGrrj2Przg6F7M_7m7MBo_Fldvi-i6YubHnNFjdNinfbJjczMHmz4lD_8u7udX5c3t5fV8dlMir9VYogAlNBXawsJybgFQSmaRSlkp1VhllOTKNkZqWXHLaGNr2YBtRK0kio5PyclX7irmr0wa28ElbfoevQnr1EqpGNTZxJT8_QJ1DClFY9vV58vxrQXafhpuvw1n9mgTul4MpvshN0ozcLwBMGnsbUSvXfrmGOT7Wd38cKhTuwzr6LOLXxZ-AGc7j_U</recordid><startdate>20090122</startdate><enddate>20090122</enddate><creator>Gemma, Sandra</creator><creator>Campiani, Giuseppe</creator><creator>Butini, Stefania</creator><creator>Joshi, Bhupendra P</creator><creator>Kukreja, Gagan</creator><creator>Coccone, Salvatore Sanna</creator><creator>Bernetti, Matteo</creator><creator>Persico, Marco</creator><creator>Nacci, Vito</creator><creator>Fiorini, Isabella</creator><creator>Novellino, Ettore</creator><creator>Taramelli, Donatella</creator><creator>Basilico, Nicoletta</creator><creator>Parapini, Silvia</creator><creator>Yardley, Vanessa</creator><creator>Croft, Simon</creator><creator>Keller-Maerki, Sonja</creator><creator>Rottmann, Matthias</creator><creator>Brun, Reto</creator><creator>Coletta, Massimiliano</creator><creator>Marini, Stefano</creator><creator>Guiso, Giovanna</creator><creator>Caccia, Silvio</creator><creator>Fattorusso, Caterina</creator><general>American Chemical Society</general><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>7X8</scope></search><sort><creationdate>20090122</creationdate><title>Combining 4-Aminoquinoline- and Clotrimazole-Based Pharmacophores toward Innovative and Potent Hybrid Antimalarials</title><author>Gemma, Sandra ; Campiani, Giuseppe ; Butini, Stefania ; Joshi, Bhupendra P ; Kukreja, Gagan ; Coccone, Salvatore Sanna ; Bernetti, Matteo ; Persico, Marco ; Nacci, Vito ; Fiorini, Isabella ; Novellino, Ettore ; Taramelli, Donatella ; Basilico, Nicoletta ; Parapini, Silvia ; Yardley, Vanessa ; Croft, Simon ; Keller-Maerki, Sonja ; Rottmann, Matthias ; Brun, Reto ; Coletta, Massimiliano ; Marini, Stefano ; Guiso, Giovanna ; Caccia, Silvio ; Fattorusso, Caterina</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a378t-a5185c05cf1bf33f11a662fa0664889f8e8638f9e6c643f209f7691f95786a5d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2009</creationdate><topic>Aminoquinolines - chemistry</topic><topic>Aminoquinolines - pharmacokinetics</topic><topic>Aminoquinolines - pharmacology</topic><topic>Animals</topic><topic>Antibiotics. 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Med. Chem</addtitle><date>2009-01-22</date><risdate>2009</risdate><volume>52</volume><issue>2</issue><spage>502</spage><epage>513</epage><pages>502-513</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><coden>JMCMAR</coden><abstract>Antimalarial agents structurally based on novel pharmacophores, synthesized by low-cost synthetic procedures and characterized by low potential for developing resistance are urgently needed. Recently, we developed an innovative class of antimalarials based on a polyaromatic pharmacophore. Hybridizing the 4-aminoquinoline or the 9-aminoacridine system of known antimalarials with the clotrimazole-like pharmacophore, characterized by a polyarylmethyl group, we describe herein the development of a unique class (4a−l and 5a−c) of antimalarials selectively interacting with free heme and interfering with Plasmodium falciparum (Pf) heme metabolism. Combination of the polyarylmethyl system, able to form and stabilize radical intermediates, with the iron-complexing and conjugation-mediated electron transfer properties of the 4(9)-aminoquinoline(acridine) system led to potent antimalarials in vitro against chloroquine sensitive and resistant Pf strains. Among the compounds synthesized, 4g was active in vivo against P. chabaudi and P. berghei after oral administration and, possessing promising pharmacokinetic properties, it is a candidate for further preclinical development.</abstract><cop>Columbus, OH</cop><pub>American Chemical Society</pub><pmid>19113955</pmid><doi>10.1021/jm801352s</doi><tpages>12</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Journal of medicinal chemistry, 2009-01, Vol.52 (2), p.502-513 |
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| source | ACS Publications; MEDLINE |
| subjects | Aminoquinolines - chemistry Aminoquinolines - pharmacokinetics Aminoquinolines - pharmacology Animals Antibiotics. Antiinfectious agents. Antiparasitic agents Antimalarials - chemical synthesis Antimalarials - pharmacokinetics Antimalarials - pharmacology Antiparasitic agents Biological and medical sciences Cell Line Clotrimazole - chemistry Clotrimazole - pharmacokinetics Clotrimazole - pharmacology Humans Magnetic Resonance Spectroscopy Medical sciences Mice Pharmacology. Drug treatments Plasmodium - drug effects Rats Species Specificity Spectrometry, Mass, Electrospray Ionization |
| title | Combining 4-Aminoquinoline- and Clotrimazole-Based Pharmacophores toward Innovative and Potent Hybrid Antimalarials |
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