title: Synthesis and antimalarial evaluation of amide and urea derivatives based on the thiaplakortone A natural product scaffold.
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.
authors.affiliation: Eskitis Institute for Drug Discovery, Griffith University, Brisbane, QLD 4111, Australia. r.davis@griffith.edu.au.
authors.forename: Brett D
authors.initials: BD
authors.lastname: Schwartz
authors.forename: Tina S
authors.initials: TS
authors.lastname: Skinner-Adams
authors.forename: Katherine T
authors.initials: KT
authors.lastname: Andrews
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Coster
authors.forename: Michael D
authors.initials: MD
authors.lastname: Edstein
authors.forename: Donna
authors.initials: D
authors.lastname: MacKenzie
authors.forename: Susan A
authors.initials: SA
authors.lastname: Charman
authors.forename: Maria
authors.initials: M
authors.lastname: Koltun
authors.forename: Scott
authors.initials: S
authors.lastname: Blundell
authors.forename: Anna
authors.initials: A
authors.lastname: Campbell
authors.forename: Rebecca H
authors.initials: RH
authors.lastname: Pouwer
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Quinn
authors.forename: Karren D
authors.initials: KD
authors.lastname: Beattie
authors.forename: Peter C
authors.initials: PC
authors.lastname: Healy
authors.forename: Rohan A
authors.initials: RA
authors.lastname: Davis
mesh_terms: D000577:Amides / Q000737:chemistry*; D000818:Animals; D000962:Antimalarials / Q000009:adverse effects / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D053626:Atovaquone / Q000494:pharmacology; D001688:Biological Products / Q000737:chemistry*; D002460:Cell Line; D060326:Chemistry Techniques, Synthetic; D004351:Drug Resistance / Q000187:drug effects; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D008288:Malaria / Q000188:drug therapy; D008297:Male; D051379:Mice; D010962:Plasmodium berghei / Q000187:drug effects / Q000502:physiology; D010963:Plasmodium falciparum / Q000187:drug effects; D013329:Structure-Activity Relationship; D014227:Triazines / Q000009:adverse effects / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D014508:Urea / Q000737:chemistry*
chemical_list: D000577:Amides; D000962:Antimalarials; D001688:Biological Products; D014227:Triazines; C000589395:thiaplakortone A; D014508:Urea; D053626:Atovaquone