Synthesis, in vitro and in vivo antimalarial assessment of sulfide, sulfone and vinyl amide-substituted 1,2,4-trioxanes prepared via thiol-olefin co-oxygenation (TOCO) of allylic alcohols

Richard Amewu; Peter Gibbons; Amira Mukhtar; Andrew V. Stachulski; Stephen A. Ward; Charlotte Hall; Karen Rimmer; Jill Davies; Livia Vivas; John Bacsa; Amy E. Mercer; Gemma Nixon; Paul A. Stocks; Paul M. O'Neill

doi:10.1039/B924319D

Synthesis, in vitro and in vivoantimalarial assessment of sulfide, sulfone and vinyl amide-substituted 1,2,4-trioxanes prepared viathiol-olefin co-oxygenation (TOCO) of allylic alcohols†

Richard Amewu,^a Peter Gibbons,^a Amira Mukhtar,^a Andrew V. Stachulski,^a Stephen A. Ward,^b Charlotte Hall,^b Karen Rimmer,^b Jill Davies,^b Livia Vivas,^d John Bacsa,^a Amy E. Mercer,^c Gemma Nixon,^b Paul A. Stocks^b and Paul M. O'Neill*^a

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^a Department of Chemistry, University of Liverpool, P.O. Box 147, Liverpool, UK
E-mail: P.M.oneill01@liv.ac.uk
Fax: (+44) 151 794 3588
Tel: (+44) 151 794 3553

^b Liverpool School of Tropical Medicine, Pembroke Place, Liverpool, UK

^c MRC Centre for Drug Safety Science, Dept of Pharmacology and Therapeutics, The University of Liverpool Sherrington Buildings, Ashton Street

^d Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UK

Abstract

Thiol-Olefin Co-Oxygenation (TOCO) methodology has been applied to the synthesis of a small library of weak base and polar 1,2,4-trioxanes. The 1,2,4-trioxane units synthesised exhibit remarkable stability as they survive base catalysed hydrolysis and mixed anhydride/amine coupling reactions. This unique stability feature has enabled a range of novel substitution patterns to be incorporated within the spiro 1,2,4-trioxane unit. Selected analogues express potent in vitro nM antimalarial activity, low cytotoxicity and oral activity in the Plasmodium berghei mouse model of malaria.

Organic & Biomolecular Chemistry

Synthesis, in vitro and in vivoantimalarial assessment of sulfide, sulfone and vinyl amide-substituted 1,2,4-trioxanes prepared viathiol-olefin co-oxygenation (TOCO) of allylic alcohols†

Abstract

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Synthesis, in vitro and in vivo antimalarial assessment of sulfide, sulfone and vinyl amide-substituted 1,2,4-trioxanes prepared via thiol-olefin co-oxygenation (TOCO) of allylic alcohols

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