Novel Selective Inhibitors of the Zinc Plasmodial Aminopeptidase PfA-M1 as Potential Antimalarial Agents
Proteases that are expressed during the erythocytic stage of Plasmodium falciparum are newly explored drug targets for the treatment of malaria. We report here the discovery of potent inhibitors of PfA-M1, a metallo-aminopeptidase of the parasite. These compounds are based on a malonic hydroxamic te...
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| Veröffentlicht in: | Journal of medicinal chemistry 2007-03, Vol.50 (6), p.1322-1334 |
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| creator | Flipo, Marion Beghyn, Terence Leroux, Virginie Florent, Isabelle Deprez, Benoit P Deprez-Poulain, Rebecca F |
| description | Proteases that are expressed during the erythocytic stage of Plasmodium falciparum are newly explored drug targets for the treatment of malaria. We report here the discovery of potent inhibitors of PfA-M1, a metallo-aminopeptidase of the parasite. These compounds are based on a malonic hydroxamic template and present a very good selectivity toward neutral aminopeptidase (APN-CD13), a related protease in mammals. Structure−activity relationships in these series are described. Further optimization of the best inhibitor yielded a nanomolar, selective inhibitor of PfA-M1. This inhibitor displays good physicochemical and pharmacokinetic properties and a promising antimalarial activity. |
| doi_str_mv | 10.1021/jm061169b |
| format | Article |
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We report here the discovery of potent inhibitors of PfA-M1, a metallo-aminopeptidase of the parasite. These compounds are based on a malonic hydroxamic template and present a very good selectivity toward neutral aminopeptidase (APN-CD13), a related protease in mammals. Structure−activity relationships in these series are described. Further optimization of the best inhibitor yielded a nanomolar, selective inhibitor of PfA-M1. This inhibitor displays good physicochemical and pharmacokinetic properties and a promising antimalarial activity.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm061169b</identifier><identifier>PMID: 17326615</identifier><identifier>CODEN: JMCMAR</identifier><language>eng</language><publisher>Washington, DC: American Chemical Society</publisher><subject>Aminopeptidases - antagonists & inhibitors ; Aminopeptidases - chemistry ; Animals ; Antibiotics. Antiinfectious agents. Antiparasitic agents ; Antimalarials - chemical synthesis ; Antimalarials - chemistry ; Antimalarials - pharmacology ; Antiparasitic agents ; Biochemistry ; Biochemistry, Molecular Biology ; Biodiversity ; Biological and medical sciences ; Cells, Cultured ; Cellular Biology ; Erythrocytes - drug effects ; Erythrocytes - parasitology ; Humans ; Hydroxamic Acids - chemical synthesis ; Hydroxamic Acids - chemistry ; Hydroxamic Acids - pharmacology ; Life Sciences ; Malonates - chemical synthesis ; Malonates - chemistry ; Malonates - pharmacology ; Medical sciences ; Metalloproteases - antagonists & inhibitors ; Metalloproteases - chemistry ; Microbiology and Parasitology ; Molecular biology ; Pharmacology. 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Med. Chem</addtitle><description>Proteases that are expressed during the erythocytic stage of Plasmodium falciparum are newly explored drug targets for the treatment of malaria. We report here the discovery of potent inhibitors of PfA-M1, a metallo-aminopeptidase of the parasite. These compounds are based on a malonic hydroxamic template and present a very good selectivity toward neutral aminopeptidase (APN-CD13), a related protease in mammals. Structure−activity relationships in these series are described. Further optimization of the best inhibitor yielded a nanomolar, selective inhibitor of PfA-M1. This inhibitor displays good physicochemical and pharmacokinetic properties and a promising antimalarial activity.</description><subject>Aminopeptidases - antagonists & inhibitors</subject><subject>Aminopeptidases - chemistry</subject><subject>Animals</subject><subject>Antibiotics. Antiinfectious agents. Antiparasitic agents</subject><subject>Antimalarials - chemical synthesis</subject><subject>Antimalarials - chemistry</subject><subject>Antimalarials - pharmacology</subject><subject>Antiparasitic agents</subject><subject>Biochemistry</subject><subject>Biochemistry, Molecular Biology</subject><subject>Biodiversity</subject><subject>Biological and medical sciences</subject><subject>Cells, Cultured</subject><subject>Cellular Biology</subject><subject>Erythrocytes - drug effects</subject><subject>Erythrocytes - parasitology</subject><subject>Humans</subject><subject>Hydroxamic Acids - chemical synthesis</subject><subject>Hydroxamic Acids - chemistry</subject><subject>Hydroxamic Acids - pharmacology</subject><subject>Life Sciences</subject><subject>Malonates - chemical synthesis</subject><subject>Malonates - chemistry</subject><subject>Malonates - pharmacology</subject><subject>Medical sciences</subject><subject>Metalloproteases - antagonists & inhibitors</subject><subject>Metalloproteases - chemistry</subject><subject>Microbiology and Parasitology</subject><subject>Molecular biology</subject><subject>Pharmacology. Drug treatments</subject><subject>Plasmodium falciparum</subject><subject>Plasmodium falciparum - drug effects</subject><subject>Plasmodium falciparum - enzymology</subject><subject>Protistology</subject><subject>Quantitative Structure-Activity Relationship</subject><subject>Solubility</subject><subject>Systematics, Phylogenetics and taxonomy</subject><subject>Zinc</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>eNqF0U2P0zAQBmALgdiycOAPIF9AAingr9jJsVoBu9CFSltA4mJNnAlxSeJipxX8e7Lbqr0gcRrZ8-jVSC8hTzl7zZngb9Y905zrsrpHZjwXLFMFU_fJjDEhMqGFPCOPUlozxiQX8iE540YKrXk-I-2nsMOO3mCHbvQ7pFdD6ys_hphoaOjYIv3uB0eXHaQ-1B46Ou_9EDa4GX0NCemymWfXnEKiyzDiMN6RafTQQbx7_Jh-02PyoIEu4ZPDPCdf3r1dXVxmi8_vry7miwyUMmOmUAngFaJmBtAUppBKQlPmUJRl1eQonXOKc5erGqBqmFHMYM2caKpSmVqek1f73BY6u4nTGfGPDeDt5Xxh-6EdLBMlU5KJHZ_wiz3exPBri2m0vU8Ouw4GDNtkDRNaCqH-C3lpcq30beLLPXQxpBSxOd7Amb0tyx7LmuyzQ-i26rE-yUM7E3h-AJAcdE2Ewfl0coXORS7l5LK982nE38c9xJ9WG2lyu1re2G_Xiw9fi9VHy0-54JJdh20cpkb-ceBfKl22jg</recordid><startdate>20070322</startdate><enddate>20070322</enddate><creator>Flipo, Marion</creator><creator>Beghyn, Terence</creator><creator>Leroux, Virginie</creator><creator>Florent, Isabelle</creator><creator>Deprez, Benoit P</creator><creator>Deprez-Poulain, Rebecca F</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>7QO</scope><scope>8FD</scope><scope>FR3</scope><scope>M7N</scope><scope>P64</scope><scope>7X8</scope><scope>1XC</scope><orcidid>https://orcid.org/0000-0003-2863-5721</orcidid><orcidid>https://orcid.org/0000-0002-7140-6417</orcidid><orcidid>https://orcid.org/0000-0002-2777-4538</orcidid><orcidid>https://orcid.org/0000-0002-3318-5297</orcidid></search><sort><creationdate>20070322</creationdate><title>Novel Selective Inhibitors of the Zinc Plasmodial Aminopeptidase PfA-M1 as Potential Antimalarial Agents</title><author>Flipo, Marion ; Beghyn, Terence ; Leroux, Virginie ; Florent, Isabelle ; Deprez, Benoit P ; Deprez-Poulain, Rebecca F</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a447t-4e42a1bee607ae7878343af95a899bf5e3ccc411c54daabf07407ed0c2fb947d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2007</creationdate><topic>Aminopeptidases - antagonists & inhibitors</topic><topic>Aminopeptidases - chemistry</topic><topic>Animals</topic><topic>Antibiotics. Antiinfectious agents. Antiparasitic agents</topic><topic>Antimalarials - chemical synthesis</topic><topic>Antimalarials - chemistry</topic><topic>Antimalarials - pharmacology</topic><topic>Antiparasitic agents</topic><topic>Biochemistry</topic><topic>Biochemistry, Molecular Biology</topic><topic>Biodiversity</topic><topic>Biological and medical sciences</topic><topic>Cells, Cultured</topic><topic>Cellular Biology</topic><topic>Erythrocytes - drug effects</topic><topic>Erythrocytes - parasitology</topic><topic>Humans</topic><topic>Hydroxamic Acids - chemical synthesis</topic><topic>Hydroxamic Acids - chemistry</topic><topic>Hydroxamic Acids - pharmacology</topic><topic>Life Sciences</topic><topic>Malonates - chemical synthesis</topic><topic>Malonates - chemistry</topic><topic>Malonates - pharmacology</topic><topic>Medical sciences</topic><topic>Metalloproteases - antagonists & inhibitors</topic><topic>Metalloproteases - chemistry</topic><topic>Microbiology and Parasitology</topic><topic>Molecular biology</topic><topic>Pharmacology. Drug treatments</topic><topic>Plasmodium falciparum</topic><topic>Plasmodium falciparum - drug effects</topic><topic>Plasmodium falciparum - enzymology</topic><topic>Protistology</topic><topic>Quantitative Structure-Activity Relationship</topic><topic>Solubility</topic><topic>Systematics, Phylogenetics and taxonomy</topic><topic>Zinc</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Flipo, Marion</creatorcontrib><creatorcontrib>Beghyn, Terence</creatorcontrib><creatorcontrib>Leroux, Virginie</creatorcontrib><creatorcontrib>Florent, Isabelle</creatorcontrib><creatorcontrib>Deprez, Benoit P</creatorcontrib><creatorcontrib>Deprez-Poulain, Rebecca F</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>Biotechnology Research Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>MEDLINE - Academic</collection><collection>Hyper Article en Ligne (HAL)</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Flipo, Marion</au><au>Beghyn, Terence</au><au>Leroux, Virginie</au><au>Florent, Isabelle</au><au>Deprez, Benoit P</au><au>Deprez-Poulain, Rebecca F</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Novel Selective Inhibitors of the Zinc Plasmodial Aminopeptidase PfA-M1 as Potential Antimalarial Agents</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2007-03-22</date><risdate>2007</risdate><volume>50</volume><issue>6</issue><spage>1322</spage><epage>1334</epage><pages>1322-1334</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><coden>JMCMAR</coden><abstract>Proteases that are expressed during the erythocytic stage of Plasmodium falciparum are newly explored drug targets for the treatment of malaria. We report here the discovery of potent inhibitors of PfA-M1, a metallo-aminopeptidase of the parasite. These compounds are based on a malonic hydroxamic template and present a very good selectivity toward neutral aminopeptidase (APN-CD13), a related protease in mammals. Structure−activity relationships in these series are described. Further optimization of the best inhibitor yielded a nanomolar, selective inhibitor of PfA-M1. This inhibitor displays good physicochemical and pharmacokinetic properties and a promising antimalarial activity.</abstract><cop>Washington, DC</cop><pub>American Chemical Society</pub><pmid>17326615</pmid><doi>10.1021/jm061169b</doi><tpages>13</tpages><orcidid>https://orcid.org/0000-0003-2863-5721</orcidid><orcidid>https://orcid.org/0000-0002-7140-6417</orcidid><orcidid>https://orcid.org/0000-0002-2777-4538</orcidid><orcidid>https://orcid.org/0000-0002-3318-5297</orcidid></addata></record> |
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| ispartof | Journal of medicinal chemistry, 2007-03, Vol.50 (6), p.1322-1334 |
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| source | ACS Publications; MEDLINE |
| subjects | Aminopeptidases - antagonists & inhibitors Aminopeptidases - chemistry Animals Antibiotics. Antiinfectious agents. Antiparasitic agents Antimalarials - chemical synthesis Antimalarials - chemistry Antimalarials - pharmacology Antiparasitic agents Biochemistry Biochemistry, Molecular Biology Biodiversity Biological and medical sciences Cells, Cultured Cellular Biology Erythrocytes - drug effects Erythrocytes - parasitology Humans Hydroxamic Acids - chemical synthesis Hydroxamic Acids - chemistry Hydroxamic Acids - pharmacology Life Sciences Malonates - chemical synthesis Malonates - chemistry Malonates - pharmacology Medical sciences Metalloproteases - antagonists & inhibitors Metalloproteases - chemistry Microbiology and Parasitology Molecular biology Pharmacology. Drug treatments Plasmodium falciparum Plasmodium falciparum - drug effects Plasmodium falciparum - enzymology Protistology Quantitative Structure-Activity Relationship Solubility Systematics, Phylogenetics and taxonomy Zinc |
| title | Novel Selective Inhibitors of the Zinc Plasmodial Aminopeptidase PfA-M1 as Potential Antimalarial Agents |
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