Design and synthesis of orally active dispiro 1,2,4,5-tetraoxanes; synthetic antimalarials with superior activity to artemisinin.
Unsymmetrical dispiro- and spirotetraoxanes have been designed and synthesized via acid-catalyzed cyclocondensation of bis(hydroperoxides) with ketones. Incorporation of water-soluble and polar functionalities, via reductive amination and amide bond formation, produces several analogues with low nanomolar in vitro antimalarial activity. Several analogues display an unprecedented level of oral antimalarial activity for this class of endoperoxide drug.
Amewu
Richard
R
Department of Chemistry, University of Liverpool, PO Box 147, Liverpool, UK L69 3BX.
Stachulski
Andrew V
AV
Ward
Stephen A
SA
Berry
Neil G
NG
Bray
Patrick G
PG
Davies
Jill
J
Labat
Gael
G
Vivas
Livia
L
O'Neill
Paul M
PM
D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000494:pharmacology*; D037621:Artemisinins / Q000494:pharmacology*; D015195:Drug Design; D008958:Models, Molecular; D015394:Molecular Structure; D010963:Plasmodium falciparum / Q000187:drug effects; D012717:Sesquiterpenes / Q000494:pharmacology*; D045568:Tetraoxanes / Q000138:chemical synthesis*
D000962:Antimalarials; D037621:Artemisinins; D012717:Sesquiterpenes; D045568:Tetraoxanes; C031327:artemisinin