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.
Bibliographical noteFunding Information:
The authors thank the EPSRC (M.P.), the BBSRC (S.A.W., P.O.N., P.A.S., Grants BB/C006321/1 and 26/B13581) and the FCT (Fundação para a Ciência e a Tecnologia) Portugal, for funding this work. We also thank Dr. J. L. Maggs (Department of Pharmacology, University of Liverpool) for carrying out the LCMS study on analogue 19b .
- Mechanism of action