Synthesis and antimalarial evaluation of amide and urea derivatives based on the thiaplakortone A natural product scaffold
A series of amide (8–32, 40–45) and urea (33, 34, 36–39) analogues based on the thiaplakortone A natural product scaffold were synthesised and screened for in vitro antimalarial activity against chloroquine-sensitive (3D7) and chloroquine- and mefloquine-resistant (Dd2) Plasmodium falciparum parasit...
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Veröffentlicht in: | Organic & biomolecular chemistry 2015-02, Vol.13 (5), p.1558-1570 |
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creator | Schwartz, Brett D Skinner-Adams, Tina S Andrews, Katherine T Coster, Mark J Edstein, Michael D MacKenzie, Donna Charman, Susan A Koltun, Maria Blundell, Scott Campbell, Anna Pouwer, Rebecca H Quinn, Ronald J Beattie, Karren D Healy, Peter C Davis, Rohan A |
description | A series of amide (8–32, 40–45) and urea (33, 34, 36–39) analogues based on the thiaplakortone A natural product scaffold were synthesised and screened for in vitro antimalarial activity against chloroquine-sensitive (3D7) and chloroquine- and mefloquine-resistant (Dd2) Plasmodium falciparum parasite lines. Several analogues displayed potent inhibition of P. falciparum growth (IC50 100). Two of these compounds, 8 and 33, exhibited good aqueous solubility and metabolic stability, and when administered subcutaneously to mice (32 mg kg(-1)), plasma concentrations remained above 0.2 μM for at least 8 h. Both 8 and 33 were well tolerated in mice after subcutaneous administration of 32 mg kg(-1) twice daily for 4 days. Using this regimen blood stage P. berghei was suppressed by 52% for 8 and 26% for 33, relative to the vehicle control. |
doi_str_mv | 10.1039/c4ob01849d |
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Several analogues displayed potent inhibition of P. falciparum growth (IC50 <500 nM) and good selectivity for P. falciparum versus human neonatal foreskin fibroblast cells (selectivity index >100). Two of these compounds, 8 and 33, exhibited good aqueous solubility and metabolic stability, and when administered subcutaneously to mice (32 mg kg(-1)), plasma concentrations remained above 0.2 μM for at least 8 h. Both 8 and 33 were well tolerated in mice after subcutaneous administration of 32 mg kg(-1) twice daily for 4 days. 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Several analogues displayed potent inhibition of P. falciparum growth (IC50 <500 nM) and good selectivity for P. falciparum versus human neonatal foreskin fibroblast cells (selectivity index >100). Two of these compounds, 8 and 33, exhibited good aqueous solubility and metabolic stability, and when administered subcutaneously to mice (32 mg kg(-1)), plasma concentrations remained above 0.2 μM for at least 8 h. Both 8 and 33 were well tolerated in mice after subcutaneous administration of 32 mg kg(-1) twice daily for 4 days. Using this regimen blood stage P. berghei was suppressed by 52% for 8 and 26% for 33, relative to the vehicle control.</description><subject>Amides - chemistry</subject><subject>Animals</subject><subject>Antimalarials - adverse effects</subject><subject>Antimalarials - chemistry</subject><subject>Antimalarials - pharmacokinetics</subject><subject>Antimalarials - pharmacology</subject><subject>Atovaquone - pharmacology</subject><subject>Biological Products - chemistry</subject><subject>Cell Line</subject><subject>Chemistry Techniques, Synthetic</subject><subject>Drug Resistance - drug effects</subject><subject>Female</subject><subject>Humans</subject><subject>Inhibitory Concentration 50</subject><subject>Malaria - drug therapy</subject><subject>Male</subject><subject>Mice</subject><subject>Plasmodium</subject><subject>Plasmodium berghei - drug effects</subject><subject>Plasmodium berghei - physiology</subject><subject>Plasmodium falciparum - drug effects</subject><subject>Structure-Activity Relationship</subject><subject>Triazines - adverse effects</subject><subject>Triazines - chemistry</subject><subject>Triazines - pharmacokinetics</subject><subject>Triazines - pharmacology</subject><subject>Urea - chemistry</subject><issn>1477-0520</issn><issn>1477-0539</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkU1r3DAQhkVIyPclP6DoGArbjL4s6ZhumzYQyCHt2YytMXHrtbaSvbD59VE325x7GGZgHl5m3pexKwGfBCh_0-rYgHDahwN2KrS1CzDKH77PEk7YWc6_AIS3lT5mJ9JoD864U_bytB2nZ8p95jiGUlO_wgFTjwOnDQ4zTn0ceew4rvpAO2hOhDxQ6jdluaHMG8wUeMGKUqke1wP-jmmKI_FbPuI0pyK3TjHM7cRzi10Xh3DBjjocMl3u-zn7eff1x_L74uHx2_3y9mHRKm-nhRKFBwlQteikMFIapcB3rTSV60jqBkJlyvuNha6pnLPWaa20RkdUlemcXb_plgP-zJSnetXnloYBR4pzrkVVFRe1N_AfqJEavFW2oB_f0DbFnBN19ToV69K2FlD_jaVe6sfPu1i-FPjDXnduVhTe0X85qFchE4hC</recordid><startdate>20150207</startdate><enddate>20150207</enddate><creator>Schwartz, Brett D</creator><creator>Skinner-Adams, Tina S</creator><creator>Andrews, Katherine T</creator><creator>Coster, Mark J</creator><creator>Edstein, Michael D</creator><creator>MacKenzie, Donna</creator><creator>Charman, Susan A</creator><creator>Koltun, Maria</creator><creator>Blundell, Scott</creator><creator>Campbell, Anna</creator><creator>Pouwer, Rebecca H</creator><creator>Quinn, Ronald J</creator><creator>Beattie, Karren D</creator><creator>Healy, Peter C</creator><creator>Davis, Rohan A</creator><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><scope>M7N</scope></search><sort><creationdate>20150207</creationdate><title>Synthesis and antimalarial evaluation of amide and urea derivatives based on the thiaplakortone A natural product scaffold</title><author>Schwartz, Brett D ; Skinner-Adams, Tina S ; Andrews, Katherine T ; Coster, Mark J ; Edstein, Michael D ; MacKenzie, Donna ; Charman, Susan A ; Koltun, Maria ; Blundell, Scott ; Campbell, Anna ; Pouwer, Rebecca H ; Quinn, Ronald J ; Beattie, Karren D ; Healy, Peter C ; Davis, Rohan A</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c397t-31caf02006ca82152253309fc2568fe24b0d65184b70fb68877844344a8ee6443</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Amides - chemistry</topic><topic>Animals</topic><topic>Antimalarials - adverse effects</topic><topic>Antimalarials - chemistry</topic><topic>Antimalarials - pharmacokinetics</topic><topic>Antimalarials - pharmacology</topic><topic>Atovaquone - pharmacology</topic><topic>Biological Products - chemistry</topic><topic>Cell Line</topic><topic>Chemistry Techniques, Synthetic</topic><topic>Drug Resistance - drug effects</topic><topic>Female</topic><topic>Humans</topic><topic>Inhibitory Concentration 50</topic><topic>Malaria - drug therapy</topic><topic>Male</topic><topic>Mice</topic><topic>Plasmodium</topic><topic>Plasmodium berghei - drug effects</topic><topic>Plasmodium berghei - physiology</topic><topic>Plasmodium falciparum - drug effects</topic><topic>Structure-Activity Relationship</topic><topic>Triazines - adverse effects</topic><topic>Triazines - chemistry</topic><topic>Triazines - pharmacokinetics</topic><topic>Triazines - pharmacology</topic><topic>Urea - chemistry</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Schwartz, Brett D</creatorcontrib><creatorcontrib>Skinner-Adams, Tina S</creatorcontrib><creatorcontrib>Andrews, Katherine T</creatorcontrib><creatorcontrib>Coster, Mark J</creatorcontrib><creatorcontrib>Edstein, Michael D</creatorcontrib><creatorcontrib>MacKenzie, Donna</creatorcontrib><creatorcontrib>Charman, Susan A</creatorcontrib><creatorcontrib>Koltun, Maria</creatorcontrib><creatorcontrib>Blundell, Scott</creatorcontrib><creatorcontrib>Campbell, Anna</creatorcontrib><creatorcontrib>Pouwer, Rebecca H</creatorcontrib><creatorcontrib>Quinn, Ronald J</creatorcontrib><creatorcontrib>Beattie, Karren D</creatorcontrib><creatorcontrib>Healy, Peter C</creatorcontrib><creatorcontrib>Davis, Rohan A</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><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><jtitle>Organic & biomolecular chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Schwartz, Brett D</au><au>Skinner-Adams, Tina S</au><au>Andrews, Katherine T</au><au>Coster, Mark J</au><au>Edstein, Michael D</au><au>MacKenzie, Donna</au><au>Charman, Susan A</au><au>Koltun, Maria</au><au>Blundell, Scott</au><au>Campbell, Anna</au><au>Pouwer, Rebecca H</au><au>Quinn, Ronald J</au><au>Beattie, Karren D</au><au>Healy, Peter C</au><au>Davis, Rohan A</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Synthesis and antimalarial evaluation of amide and urea derivatives based on the thiaplakortone A natural product scaffold</atitle><jtitle>Organic & biomolecular chemistry</jtitle><addtitle>Org Biomol Chem</addtitle><date>2015-02-07</date><risdate>2015</risdate><volume>13</volume><issue>5</issue><spage>1558</spage><epage>1570</epage><pages>1558-1570</pages><issn>1477-0520</issn><eissn>1477-0539</eissn><abstract>A series of amide (8–32, 40–45) and urea (33, 34, 36–39) analogues based on the thiaplakortone A natural product scaffold were synthesised and screened for in vitro antimalarial activity against chloroquine-sensitive (3D7) and chloroquine- and mefloquine-resistant (Dd2) Plasmodium falciparum parasite lines. Several analogues displayed potent inhibition of P. falciparum growth (IC50 <500 nM) and good selectivity for P. falciparum versus human neonatal foreskin fibroblast cells (selectivity index >100). Two of these compounds, 8 and 33, exhibited good aqueous solubility and metabolic stability, and when administered subcutaneously to mice (32 mg kg(-1)), plasma concentrations remained above 0.2 μM for at least 8 h. Both 8 and 33 were well tolerated in mice after subcutaneous administration of 32 mg kg(-1) twice daily for 4 days. Using this regimen blood stage P. berghei was suppressed by 52% for 8 and 26% for 33, relative to the vehicle control.</abstract><cop>England</cop><pmid>25490858</pmid><doi>10.1039/c4ob01849d</doi><tpages>13</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Amides - chemistry Animals Antimalarials - adverse effects Antimalarials - chemistry Antimalarials - pharmacokinetics Antimalarials - pharmacology Atovaquone - pharmacology Biological Products - chemistry Cell Line Chemistry Techniques, Synthetic Drug Resistance - drug effects Female Humans Inhibitory Concentration 50 Malaria - drug therapy Male Mice Plasmodium Plasmodium berghei - drug effects Plasmodium berghei - physiology Plasmodium falciparum - drug effects Structure-Activity Relationship Triazines - adverse effects Triazines - chemistry Triazines - pharmacokinetics Triazines - pharmacology Urea - chemistry |
title | Synthesis and antimalarial evaluation of amide and urea derivatives based on the thiaplakortone A natural product scaffold |
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