close Icon

Two-step synthesis of achiral dispiro-1,2,4,5-tetraoxanes with outstanding antimalarial activity, low toxicity, and high-stability profiles.

Ellis GL, Amewu R, Sabbani S, Stocks PA, Shone A, Stanford D, Gibbons P, Davies J, Vivas L, Charnaud S, Bongard E, Hall C, Rimmer K, Lozanom S, Jesús M, Gargallo D, Ward SA, O'Neill PM

  • Journal Journal of medicinal chemistry

  • Published 15 Mar 2008

  • Volume 51

  • ISSUE 7

  • Pagination 2170-7

  • DOI 10.1021/jm701435h


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).