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Issue 5, 2015
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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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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.

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

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The article was received on 29 Aug 2014, accepted on 26 Nov 2014 and first published on 26 Nov 2014


Article type: Paper
DOI: 10.1039/C4OB01849D
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Org. Biomol. Chem., 2015,13, 1558-1570
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    Synthesis and antimalarial evaluation of amide and urea derivatives based on the thiaplakortone A natural product scaffold

    B. D. Schwartz, T. S. Skinner-Adams, K. T. Andrews, M. J. Coster, M. D. Edstein, D. MacKenzie, S. A. Charman, M. Koltun, S. Blundell, A. Campbell, R. H. Pouwer, R. J. Quinn, K. D. Beattie, P. C. Healy and R. A. Davis, Org. Biomol. Chem., 2015, 13, 1558
    DOI: 10.1039/C4OB01849D

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