Two-step synthesis of achiral dispiro-1,2,4,5-tetraoxanes with outstanding antimalarial activity, low toxicity, and high-stability profiles.
A rapid, two-step synthesis of a range of dispiro-1,2,4,5-tetraoxanes with potent antimalarial activity both in vitro and in vivo has been achieved. These 1,2,4,5-tetraoxanes have been proven to be superior to 1,2,4-trioxolanes in terms of stability and to be superior to trioxane analogues in terms of both stability and activity. Selected analogues have in vitro nanomolar antimalarial activity and good oral activity and are nontoxic in screens for both cytotoxicity and genotoxicity. The synthesis of a fluorescent 7-nitrobenza-2-oxa-1,3-diazole (NBD) tagged tetraoxane probe and use of laser scanning confocal microscopy techniques have shown that tagged molecules accumulate selectively only in parasite infected erythrocytes and that intraparasitic formation of adducts could be inhibited by co-incubation with the iron chelator desferrioxamine (DFO).
Ellis
Gemma L
GL
Department of Chemistry, University of Liverpool, Liverpool, U.K.
Amewu
Richard
R
Sabbani
Sunil
S
Stocks
Paul A
PA
Shone
Alison
A
Stanford
Deborah
D
Gibbons
Peter
P
Davies
Jill
J
Vivas
Livia
L
Charnaud
Sarah
S
Bongard
Emily
E
Hall
Charlotte
C
Rimmer
Karen
K
Lozanom
Sonia
S
Jesús
María
M
Gargallo
Domingo
D
Ward
Stephen A
SA
O'Neill
Paul M
PM
D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002522:Chlorocebus aethiops; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004355:Drug Stability; D006801:Humans; D008297:Male; D051379:Mice; D015394:Molecular Structure; D021261:Parasitic Sensitivity Tests; D010962:Plasmodium berghei / Q000187:drug effects*; D010963:Plasmodium falciparum / Q000187:drug effects*; D051381:Rats; D012486:Salmonella typhimurium / Q000187:drug effects; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D045568:Tetraoxanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
D000962:Antimalarials; D013141:Spiro Compounds; D045568:Tetraoxanes; C423762:dispiro-1,2,4,5-tetroxane