Two-step synthesis of achiral dispiro-1,2,4,5-tetraoxanes with outstanding antimalarial activity, low toxicity, and high-stability profiles.
Gemma L Ellis, Richard Amewu, Sunil Sabbani, Paul A Stocks, Alison Shone, Deborah Stanford, Peter Gibbons, Jill Davies, Livia Vivas, Sarah Charnaud, Emily Bongard, Charlotte Hall, Karen Rimmer, Sonia Lozanom, María Jesús, Domingo Gargallo, Stephen A Ward, Paul M O'Neill
Journal of Medicinal Chemistry | Published : 2008
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..View full abstract