title: Two-step synthesis of achiral dispiro-1,2,4,5-tetraoxanes with outstanding antimalarial activity, low toxicity, and high-stability profiles.
abstract: 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).
authors.affiliation: Department of Chemistry, University of Liverpool, Liverpool, U.K.
authors.forename: Gemma L
authors.initials: GL
authors.lastname: Ellis
authors.forename: Richard
authors.initials: R
authors.lastname: Amewu
authors.forename: Sunil
authors.initials: S
authors.lastname: Sabbani
authors.forename: Paul A
authors.initials: PA
authors.lastname: Stocks
authors.forename: Alison
authors.initials: A
authors.lastname: Shone
authors.forename: Deborah
authors.initials: D
authors.lastname: Stanford
authors.forename: Peter
authors.initials: P
authors.lastname: Gibbons
authors.forename: Jill
authors.initials: J
authors.lastname: Davies
authors.forename: Livia
authors.initials: L
authors.lastname: Vivas
authors.forename: Sarah
authors.initials: S
authors.lastname: Charnaud
authors.forename: Emily
authors.initials: E
authors.lastname: Bongard
authors.forename: Charlotte
authors.initials: C
authors.lastname: Hall
authors.forename: Karen
authors.initials: K
authors.lastname: Rimmer
authors.forename: Sonia
authors.initials: S
authors.lastname: Lozanom
authors.forename: María
authors.initials: M
authors.lastname: Jesús
authors.forename: Domingo
authors.initials: D
authors.lastname: Gargallo
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Ward
authors.forename: Paul M
authors.initials: PM
authors.lastname: O'Neill
mesh_terms: 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*
chemical_list: D000962:Antimalarials; D013141:Spiro Compounds; D045568:Tetraoxanes; C423762:dispiro-1,2,4,5-tetroxane