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  • Synthesis and antimalarial evaluation of amide and urea derivatives based on the thiaplakortone A natural product scaffold

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    Author(s)
    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
    Griffith University Author(s)
    Healy, Peter C.
    Quinn, Ronald J.
    Andrews, Katherine T.
    Davis, Rohan A.
    Skinner-Adams, Tina
    Mitchell, Karren D.
    Year published
    2015
    Metadata
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    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 ...
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    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.
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    Journal Title
    Organic & Biomolecular Chemistry
    Volume
    13
    Issue
    5
    DOI
    https://doi.org/10.1039/c4ob01849d
    Copyright Statement
    © The Author(s) 2015. This is an Open Access article distributed under the terms of the Creative Commons Attribution 3.0 Unported (CC BY 3.0) License (https://creativecommons.org/licenses/by/3.0/) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
    Subject
    Medicinal and biomolecular chemistry
    Medicinal and biomolecular chemistry not elsewhere classified
    Organic chemistry
    Publication URI
    http://hdl.handle.net/10072/101276
    Collection
    • Journal articles

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