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.
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.
Amewu
Richard
R
Department of Chemistry, University of Liverpool, P.O. Box 147, Liverpool, UK L69 3BX.
Gibbons
Peter
P
Mukhtar
Amira
A
Stachulski
Andrew V
AV
Ward
Stephen A
SA
Hall
Charlotte
C
Rimmer
Karen
K
Davies
Jill
J
Vivas
Livia
L
Bacsa
John
J
Mercer
Amy E
AE
Nixon
Gemma
G
Stocks
Paul A
PA
O'Neill
Paul M
PM
D000475:Alkenes / Q000737:chemistry*; D000577:Amides / Q000737:chemistry; D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D004195:Disease Models, Animal; D006571:Heterocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008288:Malaria / Q000188:drug therapy*; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D010084:Oxidation-Reduction; D010100:Oxygen / Q000737:chemistry; D021261:Parasitic Sensitivity Tests; D010962:Plasmodium berghei / Q000187:drug effects; D020005:Propanols / Q000737:chemistry*; D013237:Stereoisomerism; D013438:Sulfhydryl Compounds / Q000737:chemistry*; D013440:Sulfides / Q000737:chemistry; D013450:Sulfones / Q000737:chemistry
C503429:1,2,4-trioxane; D000475:Alkenes; D000577:Amides; D000962:Antimalarials; D006571:Heterocyclic Compounds; D020005:Propanols; D013438:Sulfhydryl Compounds; D013440:Sulfides; D013450:Sulfones; C006463:allyl alcohol; D010100:Oxygen