Squaric acid/4-aminoquinoline conjugates: Novel potent antiplasmodial agents
We report the synthesis and structure–activity relationship (SAR) analysis of a series of hybrid compounds containing a squaric moiety conjugated with heterocyclic moieties from well-known antimalarials. This novel series of compounds presents improved antiplasmodial activity compared with the squar...
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| Veröffentlicht in: | European journal of medicinal chemistry 2013-11, Vol.69, p.365-372 |
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| container_title | European journal of medicinal chemistry |
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| creator | Ribeiro, Carlos J.A. Kumar, S. Praveen Gut, Jiri Gonçalves, Lídia M. Rosenthal, Philip J. Moreira, Rui Santos, Maria M.M. |
| description | We report the synthesis and structure–activity relationship (SAR) analysis of a series of hybrid compounds containing a squaric moiety conjugated with heterocyclic moieties from well-known antimalarials. This novel series of compounds presents improved antiplasmodial activity compared with the squaric derivatives described in our previous work. Three compounds, 8b (IC50 = 99 nM), 8c (IC50 = 95 nM), and 8d (IC50 = 105 nM) had greater in vitro potency than chloroquine 1 (IC50 = 140 nM) against chloroquine resistant Plasmodium falciparum. In addition, they were noncytotoxic against NIH 3T3 and Hek 293T cells.
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•Squaric acid/4-aminoquinoline conjugates were synthesized.•Compounds were evaluated against papain, falcipain-2 and Pf W2.•Three compounds had higher in vitro potency than chloroquine.•The most active compounds were noncytotoxic. |
| doi_str_mv | 10.1016/j.ejmech.2013.08.037 |
| format | Article |
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•Squaric acid/4-aminoquinoline conjugates were synthesized.•Compounds were evaluated against papain, falcipain-2 and Pf W2.•Three compounds had higher in vitro potency than chloroquine.•The most active compounds were noncytotoxic.</description><identifier>ISSN: 0223-5234</identifier><identifier>EISSN: 1768-3254</identifier><identifier>DOI: 10.1016/j.ejmech.2013.08.037</identifier><identifier>PMID: 24077527</identifier><language>eng</language><publisher>France: Elsevier Masson SAS</publisher><subject>4-Aminoquinoline ; Aminoquinolines - chemistry ; Aminoquinolines - pharmacology ; Animals ; Antimalarials - chemical synthesis ; Antimalarials - chemistry ; Antimalarials - pharmacology ; Antiplasmodial activity ; Cyclobutanes - chemistry ; Cyclobutanes - pharmacology ; Dose-Response Relationship, Drug ; HEK293 Cells ; Humans ; Hybrid ; Malaria ; Mice ; Molecular Structure ; NIH 3T3 Cells ; Parasitic Sensitivity Tests ; Plasmodium falciparum - drug effects ; Squaramide ; Structure-Activity Relationship</subject><ispartof>European journal of medicinal chemistry, 2013-11, Vol.69, p.365-372</ispartof><rights>2013 Elsevier Masson SAS</rights><rights>Copyright © 2013 Elsevier Masson SAS. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c362t-5aab8787a65f4f0db00bacf7cb86ac60881dabaa2fe9d9a26bb1eded7c3072f33</citedby><cites>FETCH-LOGICAL-c362t-5aab8787a65f4f0db00bacf7cb86ac60881dabaa2fe9d9a26bb1eded7c3072f33</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0223523413005540$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24077527$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ribeiro, Carlos J.A.</creatorcontrib><creatorcontrib>Kumar, S. Praveen</creatorcontrib><creatorcontrib>Gut, Jiri</creatorcontrib><creatorcontrib>Gonçalves, Lídia M.</creatorcontrib><creatorcontrib>Rosenthal, Philip J.</creatorcontrib><creatorcontrib>Moreira, Rui</creatorcontrib><creatorcontrib>Santos, Maria M.M.</creatorcontrib><title>Squaric acid/4-aminoquinoline conjugates: Novel potent antiplasmodial agents</title><title>European journal of medicinal chemistry</title><addtitle>Eur J Med Chem</addtitle><description>We report the synthesis and structure–activity relationship (SAR) analysis of a series of hybrid compounds containing a squaric moiety conjugated with heterocyclic moieties from well-known antimalarials. This novel series of compounds presents improved antiplasmodial activity compared with the squaric derivatives described in our previous work. Three compounds, 8b (IC50 = 99 nM), 8c (IC50 = 95 nM), and 8d (IC50 = 105 nM) had greater in vitro potency than chloroquine 1 (IC50 = 140 nM) against chloroquine resistant Plasmodium falciparum. In addition, they were noncytotoxic against NIH 3T3 and Hek 293T cells.
[Display omitted]
•Squaric acid/4-aminoquinoline conjugates were synthesized.•Compounds were evaluated against papain, falcipain-2 and Pf W2.•Three compounds had higher in vitro potency than chloroquine.•The most active compounds were noncytotoxic.</description><subject>4-Aminoquinoline</subject><subject>Aminoquinolines - chemistry</subject><subject>Aminoquinolines - pharmacology</subject><subject>Animals</subject><subject>Antimalarials - chemical synthesis</subject><subject>Antimalarials - chemistry</subject><subject>Antimalarials - pharmacology</subject><subject>Antiplasmodial activity</subject><subject>Cyclobutanes - chemistry</subject><subject>Cyclobutanes - pharmacology</subject><subject>Dose-Response Relationship, Drug</subject><subject>HEK293 Cells</subject><subject>Humans</subject><subject>Hybrid</subject><subject>Malaria</subject><subject>Mice</subject><subject>Molecular Structure</subject><subject>NIH 3T3 Cells</subject><subject>Parasitic Sensitivity Tests</subject><subject>Plasmodium falciparum - drug effects</subject><subject>Squaramide</subject><subject>Structure-Activity Relationship</subject><issn>0223-5234</issn><issn>1768-3254</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kE1Lw0AQhhdRbK3-A5EcvSTO7ibZ1IMgxS8oelDPy2R3Ujfko80mBf-9Ka0ehWEGhnfmnXkYu-QQceDpTRlRWZP5igRwGUEWgVRHbMpVmoVSJPExm4IQMkyEjCfszPsSAJIU4JRNRAxKJUJN2fJ9M2DnTIDG2Zs4xNo17WYYU-UaCkzblMMKe_K3wWu7pSpYtz01fYBN79YV-rq1DqsAV2PTn7OTAitPF4c6Y5-PDx-L53D59vSyuF-GRqaiDxPEPFOZwjQp4gJsDpCjKZTJsxRNClnGLeaIoqC5naNI85yTJauMBCUKKWfser933Y23ku917byhqsKG2sFrHsdzoYQcY8bivdR0rfcdFXrduRq7b81B7zjqUu856h1HDZkeOY5jVweHIa_J_g39ghsFd3sBjX9uHXXaG0eNIes6Mr22rfvf4QecioeZ</recordid><startdate>20131101</startdate><enddate>20131101</enddate><creator>Ribeiro, Carlos J.A.</creator><creator>Kumar, S. Praveen</creator><creator>Gut, Jiri</creator><creator>Gonçalves, Lídia M.</creator><creator>Rosenthal, Philip J.</creator><creator>Moreira, Rui</creator><creator>Santos, Maria M.M.</creator><general>Elsevier Masson SAS</general><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>20131101</creationdate><title>Squaric acid/4-aminoquinoline conjugates: Novel potent antiplasmodial agents</title><author>Ribeiro, Carlos J.A. ; Kumar, S. Praveen ; Gut, Jiri ; Gonçalves, Lídia M. ; Rosenthal, Philip J. ; Moreira, Rui ; Santos, Maria M.M.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c362t-5aab8787a65f4f0db00bacf7cb86ac60881dabaa2fe9d9a26bb1eded7c3072f33</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>4-Aminoquinoline</topic><topic>Aminoquinolines - chemistry</topic><topic>Aminoquinolines - pharmacology</topic><topic>Animals</topic><topic>Antimalarials - chemical synthesis</topic><topic>Antimalarials - chemistry</topic><topic>Antimalarials - pharmacology</topic><topic>Antiplasmodial activity</topic><topic>Cyclobutanes - chemistry</topic><topic>Cyclobutanes - pharmacology</topic><topic>Dose-Response Relationship, Drug</topic><topic>HEK293 Cells</topic><topic>Humans</topic><topic>Hybrid</topic><topic>Malaria</topic><topic>Mice</topic><topic>Molecular Structure</topic><topic>NIH 3T3 Cells</topic><topic>Parasitic Sensitivity Tests</topic><topic>Plasmodium falciparum - drug effects</topic><topic>Squaramide</topic><topic>Structure-Activity Relationship</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ribeiro, Carlos J.A.</creatorcontrib><creatorcontrib>Kumar, S. Praveen</creatorcontrib><creatorcontrib>Gut, Jiri</creatorcontrib><creatorcontrib>Gonçalves, Lídia M.</creatorcontrib><creatorcontrib>Rosenthal, Philip J.</creatorcontrib><creatorcontrib>Moreira, Rui</creatorcontrib><creatorcontrib>Santos, Maria M.M.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>European journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ribeiro, Carlos J.A.</au><au>Kumar, S. Praveen</au><au>Gut, Jiri</au><au>Gonçalves, Lídia M.</au><au>Rosenthal, Philip J.</au><au>Moreira, Rui</au><au>Santos, Maria M.M.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Squaric acid/4-aminoquinoline conjugates: Novel potent antiplasmodial agents</atitle><jtitle>European journal of medicinal chemistry</jtitle><addtitle>Eur J Med Chem</addtitle><date>2013-11-01</date><risdate>2013</risdate><volume>69</volume><spage>365</spage><epage>372</epage><pages>365-372</pages><issn>0223-5234</issn><eissn>1768-3254</eissn><abstract>We report the synthesis and structure–activity relationship (SAR) analysis of a series of hybrid compounds containing a squaric moiety conjugated with heterocyclic moieties from well-known antimalarials. This novel series of compounds presents improved antiplasmodial activity compared with the squaric derivatives described in our previous work. Three compounds, 8b (IC50 = 99 nM), 8c (IC50 = 95 nM), and 8d (IC50 = 105 nM) had greater in vitro potency than chloroquine 1 (IC50 = 140 nM) against chloroquine resistant Plasmodium falciparum. In addition, they were noncytotoxic against NIH 3T3 and Hek 293T cells.
[Display omitted]
•Squaric acid/4-aminoquinoline conjugates were synthesized.•Compounds were evaluated against papain, falcipain-2 and Pf W2.•Three compounds had higher in vitro potency than chloroquine.•The most active compounds were noncytotoxic.</abstract><cop>France</cop><pub>Elsevier Masson SAS</pub><pmid>24077527</pmid><doi>10.1016/j.ejmech.2013.08.037</doi><tpages>8</tpages></addata></record> |
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| ispartof | European journal of medicinal chemistry, 2013-11, Vol.69, p.365-372 |
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| language | eng |
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| subjects | 4-Aminoquinoline Aminoquinolines - chemistry Aminoquinolines - pharmacology Animals Antimalarials - chemical synthesis Antimalarials - chemistry Antimalarials - pharmacology Antiplasmodial activity Cyclobutanes - chemistry Cyclobutanes - pharmacology Dose-Response Relationship, Drug HEK293 Cells Humans Hybrid Malaria Mice Molecular Structure NIH 3T3 Cells Parasitic Sensitivity Tests Plasmodium falciparum - drug effects Squaramide Structure-Activity Relationship |
| title | Squaric acid/4-aminoquinoline conjugates: Novel potent antiplasmodial agents |
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