ABSTRACT
Dispiro N-Boc-protected 1,2,4-trioxane 2 was synthesised via Mo(acac)(2) catalysed perhydrolysis of N-Boc spirooxirane followed by condensation of the resulting beta-hydroperoxy alcohol 10 with 2-adamantanone. N-Boc 1,2,4-trioxane 2 was converted to the amine 1,2,4-trioxane hydrochloride salt 3 which was subsequently used to prepare derivatives (4-7). Several of these novel 1,2,4-trioxanes had nanomolar antimalarial activity versus the 3D7 strain of Plasmodium falciparum. Amine intermediate 3 represents a versatile derivative for the preparation of achiral arrays of trioxane analogues with antimalarial activity.
Subject(s)
Antimalarials/chemistry , Piperidines/chemistry , Animals , Antimalarials/pharmacology , Chromatography, Thin Layer , Magnetic Resonance Spectroscopy , Mass Spectrometry , Piperidines/pharmacology , Plasmodium falciparum/drug effectsABSTRACT
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).
Subject(s)
Antimalarials/chemical synthesis , Antimalarials/pharmacology , Plasmodium berghei/drug effects , Plasmodium falciparum/drug effects , Spiro Compounds/chemical synthesis , Spiro Compounds/pharmacology , Tetraoxanes/chemical synthesis , Tetraoxanes/pharmacology , Animals , Antimalarials/chemistry , Chlorocebus aethiops , Disease Models, Animal , Dose-Response Relationship, Drug , Drug Stability , Humans , Male , Mice , Molecular Structure , Parasitic Sensitivity Tests , Rats , Salmonella typhimurium/drug effects , Spiro Compounds/chemistry , Stereoisomerism , Structure-Activity Relationship , Tetraoxanes/chemistryABSTRACT
Here we present an efficient route into synthetically challenging bridged 1,2,4,5-tetraoxanes. The key to the success of this route is the use of H(2)O(2) and catalytic I(2) to form the gem-dihydroperoxide followed by a Ag(2)O mediated alkylation using 1,3-diiodopropane. Using this methodology a range of bridged tetraoxanes which display good in vitro antimalarial activity were synthesized.
