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
Hauptverfasser: 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
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container_end_page 1570
container_issue 5
container_start_page 1558
container_title Organic & biomolecular chemistry
container_volume 13
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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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 &amp; 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. 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source MEDLINE; Royal Society Of Chemistry Journals 2008-; Alma/SFX Local Collection
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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