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

Brett D Schwartz, Tina S Skinner-Adams, Katherine T Andrews, Mark J Coster, Michael D Edstein, Donna MacKenzie, Susan A Charman, Maria Koltun, Scott Blundell, Anna Campbell, Rebecca H Pouwer, Ronald J Quinn, Karren D Beattie, Peter C Healy, Rohan A Davis

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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.
Original languageEnglish
Pages (from-to)1558-1570
Number of pages13
JournalOrganic and Biomolecular Chemistry
Issue number5
Publication statusPublished - 2015

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