Diels-Alder/thiol-olefin co-oxygenation approach to antimalarials incorporating the 2,3-dioxabicyclo[3.3.1]nonane pharmacophore |
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Authors: | O'Neill Paul M Verissimo Edite Ward Stephen A Davies Jill Korshin Edward E Araujo Nuna Pugh Matthew D Cristiano M Lurdes S Stocks Paul A Bachi Mario D |
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Affiliation: | Department of Chemistry, University of Liverpool, PO Box 147, Liverpool L69 3BX, UK. P.M.oneill01@liv.ac.uk |
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Abstract: | 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. |
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