Diels-Alder/thiol-olefin co-oxygenation approach to antimalarials incorporating the 2,3-dioxabicyclo[3.3.1]nonane pharmacophore.
A Diels-Alder/thiol-olefin co-oxygenation approach to the synthesis of novel bicyclic endoperoxides 17a-22b is reported. Some of these endoperoxides (e.g., 17b, 19b, 22a and 22b) have potent nanomolar in vitro antimalarial activity equivalent to that of the synthetic antimalarial agent arteflene. Iron(II)-mediated degradation of sulfone-endoperoxide 19b and spin-trapping with TEMPO provide a spin-trapped adduct 25 indicative of the formation of a secondary carbon centered radical species 24. Reactive C-radical intermediates of this type may be involved in the expression of the antimalarial effect of these bicyclic endoperoxides.
O'Neill
Paul M
PM
Department of Chemistry, University of Liverpool, PO Box 147, Liverpool L69 3BX, UK. P.M.oneill01@liv.ac.uk
Verissimo
Edite
E
Ward
Stephen A
SA
Davies
Jill
J
Korshin
Edward E
EE
Araujo
Nuna
N
Pugh
Matthew D
MD
Cristiano
M Lurdes S
ML
Stocks
Paul A
PA
Bachi
Mario D
MD
D000473:Alkanes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D000475:Alkenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D003500:Cyclization; D053138:Cyclohexenes; D004852:Epoxy Compounds / Q000737:chemistry; D000077222:Limonene; D015394:Molecular Structure; D010100:Oxygen / Q000737:chemistry*; D010545:Peroxides / Q000737:chemistry; D010962:Plasmodium berghei / Q000187:drug effects; D013329:Structure-Activity Relationship; D013438:Sulfhydryl Compounds / Q000737:chemistry*; D013729:Terpenes / Q000737:chemistry
D000473:Alkanes; D000475:Alkenes; D000962:Antimalarials; D053138:Cyclohexenes; D004852:Epoxy Compounds; D010545:Peroxides; D013438:Sulfhydryl Compounds; D013729:Terpenes; D000077222:Limonene; D010100:Oxygen; C017573:nonane