Design, Synthesis, and Development of Novel Guaianolide-Endoperoxides as Potential Antimalarial Agents
Design and synthesis of a guaianolide-endoperoxide (thaperoxide) 3 was pursued as a new antimalarial lead which was found to be noncytotoxic as compared to the natural product lead thapsigargin 2. Several analogues of 3 were successfully synthesized and found to be comparable to derivatives of artem...
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| Veröffentlicht in: | Journal of medicinal chemistry 2010-11, Vol.53 (21), p.7864-7868 |
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| container_end_page | 7868 |
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| container_issue | 21 |
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| container_title | Journal of medicinal chemistry |
| container_volume | 53 |
| creator | Sun, Lingzhi Shah, Falgun Helal, Mohamed A Wu, Yunshan Pedduri, Yakambram Chittiboyina, Amar G Gut, Jiri Rosenthal, Philip J Avery, Mitchell A |
| description | Design and synthesis of a guaianolide-endoperoxide (thaperoxide) 3 was pursued as a new antimalarial lead which was found to be noncytotoxic as compared to the natural product lead thapsigargin 2. Several analogues of 3 were successfully synthesized and found to be comparable to derivatives of artemisinin 1 in in vitro antimalarial assay. Among the synthesized compounds, 22 showed excellent in vitro potency against the cultured parasites (W2 IC50 = 13 nM) without apparent cytotoxicity. Furthermore, SAR trends in thaperoxide analogues are presented and explained with the help of docking studies in the homology model of PfSERCA(PfATP6). |
| doi_str_mv | 10.1021/jm1006462 |
| format | Article |
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Several analogues of 3 were successfully synthesized and found to be comparable to derivatives of artemisinin 1 in in vitro antimalarial assay. Among the synthesized compounds, 22 showed excellent in vitro potency against the cultured parasites (W2 IC50 = 13 nM) without apparent cytotoxicity. Furthermore, SAR trends in thaperoxide analogues are presented and explained with the help of docking studies in the homology model of PfSERCA(PfATP6).</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm1006462</identifier><identifier>PMID: 20945914</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Animals ; Antimalarials - chemical synthesis ; Antimalarials - chemistry ; Antimalarials - pharmacology ; Artemisinins - pharmacology ; Cercopithecus aethiops ; Drug Design ; Hydrophobic and Hydrophilic Interactions ; Models, Molecular ; Parasitic Sensitivity Tests ; Peroxides - chemical synthesis ; Peroxides - chemistry ; Peroxides - pharmacology ; Plasmodium falciparum - drug effects ; Sarcoplasmic Reticulum Calcium-Transporting ATPases - chemistry ; Sesquiterpenes, Guaiane - chemical synthesis ; Sesquiterpenes, Guaiane - chemistry ; Sesquiterpenes, Guaiane - pharmacology ; Stereoisomerism ; Structure-Activity Relationship ; Thapsigargin - chemical synthesis ; Thapsigargin - chemistry ; Thapsigargin - pharmacology ; Vero Cells</subject><ispartof>Journal of medicinal chemistry, 2010-11, Vol.53 (21), p.7864-7868</ispartof><rights>Copyright © 2010 American Chemical Society</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a314t-4b9fe79ac0def0497fd78c97488d3886a26904a68fc551c18e498c2281e6a8803</citedby><cites>FETCH-LOGICAL-a314t-4b9fe79ac0def0497fd78c97488d3886a26904a68fc551c18e498c2281e6a8803</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/jm1006462$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm1006462$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,776,780,2752,27053,27901,27902,56713,56763</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/20945914$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Sun, Lingzhi</creatorcontrib><creatorcontrib>Shah, Falgun</creatorcontrib><creatorcontrib>Helal, Mohamed A</creatorcontrib><creatorcontrib>Wu, Yunshan</creatorcontrib><creatorcontrib>Pedduri, Yakambram</creatorcontrib><creatorcontrib>Chittiboyina, Amar G</creatorcontrib><creatorcontrib>Gut, Jiri</creatorcontrib><creatorcontrib>Rosenthal, Philip J</creatorcontrib><creatorcontrib>Avery, Mitchell A</creatorcontrib><title>Design, Synthesis, and Development of Novel Guaianolide-Endoperoxides as Potential Antimalarial Agents</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>Design and synthesis of a guaianolide-endoperoxide (thaperoxide) 3 was pursued as a new antimalarial lead which was found to be noncytotoxic as compared to the natural product lead thapsigargin 2. Several analogues of 3 were successfully synthesized and found to be comparable to derivatives of artemisinin 1 in in vitro antimalarial assay. Among the synthesized compounds, 22 showed excellent in vitro potency against the cultured parasites (W2 IC50 = 13 nM) without apparent cytotoxicity. Furthermore, SAR trends in thaperoxide analogues are presented and explained with the help of docking studies in the homology model of PfSERCA(PfATP6).</description><subject>Animals</subject><subject>Antimalarials - chemical synthesis</subject><subject>Antimalarials - chemistry</subject><subject>Antimalarials - pharmacology</subject><subject>Artemisinins - pharmacology</subject><subject>Cercopithecus aethiops</subject><subject>Drug Design</subject><subject>Hydrophobic and Hydrophilic Interactions</subject><subject>Models, Molecular</subject><subject>Parasitic Sensitivity Tests</subject><subject>Peroxides - chemical synthesis</subject><subject>Peroxides - chemistry</subject><subject>Peroxides - pharmacology</subject><subject>Plasmodium falciparum - drug effects</subject><subject>Sarcoplasmic Reticulum Calcium-Transporting ATPases - chemistry</subject><subject>Sesquiterpenes, Guaiane - chemical synthesis</subject><subject>Sesquiterpenes, Guaiane - chemistry</subject><subject>Sesquiterpenes, Guaiane - pharmacology</subject><subject>Stereoisomerism</subject><subject>Structure-Activity Relationship</subject><subject>Thapsigargin - chemical synthesis</subject><subject>Thapsigargin - chemistry</subject><subject>Thapsigargin - pharmacology</subject><subject>Vero Cells</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNptkMFLwzAYxYMobk4P_gOSiwdh1S9p2iZH2eYUhgrquWRpMjvapCSduP_e6HQnT-97Hz8ej4fQOYFrApTcrFsCkLOcHqAhySgkjAM7REMAShOa03SATkJYA0BKaHqMBhQEywRhQ2SmOtQrO8YvW9u_xzuMsbQVnuoP3biu1bbHzuBHFy2eb2QtrWvqSiczW7lOe_cZTcAy4GfXR7iWDb6N0spG-h-zit9wio6MbII--9URerubvU7uk8XT_GFyu0hkSlifsKUwuhBSQaUNMFGYquBKFIzzKuU8lzQXwGTOjcoyogjXTHBFKSc6l5xDOkJXu1zlXQhem7LzsYvflgTK763K_VaRvdix3WbZ6mpP_o0TgcsdIFUo127jbaz-T9AXnhpwDA</recordid><startdate>20101111</startdate><enddate>20101111</enddate><creator>Sun, Lingzhi</creator><creator>Shah, Falgun</creator><creator>Helal, Mohamed A</creator><creator>Wu, Yunshan</creator><creator>Pedduri, Yakambram</creator><creator>Chittiboyina, Amar G</creator><creator>Gut, Jiri</creator><creator>Rosenthal, Philip J</creator><creator>Avery, Mitchell A</creator><general>American Chemical Society</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></search><sort><creationdate>20101111</creationdate><title>Design, Synthesis, and Development of Novel Guaianolide-Endoperoxides as Potential Antimalarial Agents</title><author>Sun, Lingzhi ; Shah, Falgun ; Helal, Mohamed A ; Wu, Yunshan ; Pedduri, Yakambram ; Chittiboyina, Amar G ; Gut, Jiri ; Rosenthal, Philip J ; Avery, Mitchell A</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a314t-4b9fe79ac0def0497fd78c97488d3886a26904a68fc551c18e498c2281e6a8803</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2010</creationdate><topic>Animals</topic><topic>Antimalarials - chemical synthesis</topic><topic>Antimalarials - chemistry</topic><topic>Antimalarials - pharmacology</topic><topic>Artemisinins - pharmacology</topic><topic>Cercopithecus aethiops</topic><topic>Drug Design</topic><topic>Hydrophobic and Hydrophilic Interactions</topic><topic>Models, Molecular</topic><topic>Parasitic Sensitivity Tests</topic><topic>Peroxides - chemical synthesis</topic><topic>Peroxides - chemistry</topic><topic>Peroxides - pharmacology</topic><topic>Plasmodium falciparum - drug effects</topic><topic>Sarcoplasmic Reticulum Calcium-Transporting ATPases - chemistry</topic><topic>Sesquiterpenes, Guaiane - chemical synthesis</topic><topic>Sesquiterpenes, Guaiane - chemistry</topic><topic>Sesquiterpenes, Guaiane - pharmacology</topic><topic>Stereoisomerism</topic><topic>Structure-Activity Relationship</topic><topic>Thapsigargin - chemical synthesis</topic><topic>Thapsigargin - chemistry</topic><topic>Thapsigargin - pharmacology</topic><topic>Vero Cells</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Sun, Lingzhi</creatorcontrib><creatorcontrib>Shah, Falgun</creatorcontrib><creatorcontrib>Helal, Mohamed A</creatorcontrib><creatorcontrib>Wu, Yunshan</creatorcontrib><creatorcontrib>Pedduri, Yakambram</creatorcontrib><creatorcontrib>Chittiboyina, Amar G</creatorcontrib><creatorcontrib>Gut, Jiri</creatorcontrib><creatorcontrib>Rosenthal, Philip J</creatorcontrib><creatorcontrib>Avery, Mitchell A</creatorcontrib><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>Sun, Lingzhi</au><au>Shah, Falgun</au><au>Helal, Mohamed A</au><au>Wu, Yunshan</au><au>Pedduri, Yakambram</au><au>Chittiboyina, Amar G</au><au>Gut, Jiri</au><au>Rosenthal, Philip J</au><au>Avery, Mitchell A</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Design, Synthesis, and Development of Novel Guaianolide-Endoperoxides as Potential Antimalarial Agents</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2010-11-11</date><risdate>2010</risdate><volume>53</volume><issue>21</issue><spage>7864</spage><epage>7868</epage><pages>7864-7868</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>Design and synthesis of a guaianolide-endoperoxide (thaperoxide) 3 was pursued as a new antimalarial lead which was found to be noncytotoxic as compared to the natural product lead thapsigargin 2. Several analogues of 3 were successfully synthesized and found to be comparable to derivatives of artemisinin 1 in in vitro antimalarial assay. Among the synthesized compounds, 22 showed excellent in vitro potency against the cultured parasites (W2 IC50 = 13 nM) without apparent cytotoxicity. Furthermore, SAR trends in thaperoxide analogues are presented and explained with the help of docking studies in the homology model of PfSERCA(PfATP6).</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>20945914</pmid><doi>10.1021/jm1006462</doi><tpages>5</tpages></addata></record> |
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| source | ACS Publications; MEDLINE |
| subjects | Animals Antimalarials - chemical synthesis Antimalarials - chemistry Antimalarials - pharmacology Artemisinins - pharmacology Cercopithecus aethiops Drug Design Hydrophobic and Hydrophilic Interactions Models, Molecular Parasitic Sensitivity Tests Peroxides - chemical synthesis Peroxides - chemistry Peroxides - pharmacology Plasmodium falciparum - drug effects Sarcoplasmic Reticulum Calcium-Transporting ATPases - chemistry Sesquiterpenes, Guaiane - chemical synthesis Sesquiterpenes, Guaiane - chemistry Sesquiterpenes, Guaiane - pharmacology Stereoisomerism Structure-Activity Relationship Thapsigargin - chemical synthesis Thapsigargin - chemistry Thapsigargin - pharmacology Vero Cells |
| title | Design, Synthesis, and Development of Novel Guaianolide-Endoperoxides as Potential Antimalarial Agents |
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