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Browsing by Author "Barton, Victoria"

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  • Endoperoxide carbonyl falcipain 2/3 inhibitor hybrids: toward combination chemotherapy of malaria through a single chemical entity
    Publication . Gibbons, Peter D.; Verissimo, Edite; Araujo, Nuna C. P.; Barton, Victoria; Nixon, Gemma L.; Amewu, Richard K.; Chadwick, J.; Stocks, Paul A.; Biagini, Giancarlo A.; Srivastava, Abhishek; Rosenthal, Philip J.; Gut, Jiri; Guedes, Rita C.; Moreira, Rui; Sharma, Raman; Berry, Neil; Cristiano, Maria Lurdes Santos; Shone, Alison E.; Ward, Stephen A.; O'Neill, Paul M.
    We extend our approach of combination chemotherapy through a single prodrug entity (O’Neill et al. Angew. Chem., Int. Ed. 2004, 43, 4193) by using a 1,2,4-trioxolane as a protease inhibitor carbonylmasking group. These molecules are designed to target the malaria parasite through two independent mechanisms of action: iron(II) decomposition releases the carbonyl protease inhibitor and potentially cytotoxic C-radical species in tandem. Using a proposed target “heme”, we also demonstrate heme alkylation/carbonyl inhibitor release and quantitatively measure endoperoxide turnover in parasitized red blood cells.
    2010Journal article Restricted access Show more
  • Semi-synthetic and synthetic 1,2,4-trioxaquines and 1,2,4-trioxolaquines: synthesis, preliminary SAR and comparison with acridine endoperoxide conjugates
    Publication . Araujo, Nuna C. P.; Barton, Victoria; Jones, Michael; Stocks, Paul A.; Ward, Stephen A.; Davies, Jill; Bray, Patrick G.; Shone, Alison E.; Cristiano, Maria Lurdes Santos; O'Neill, Paul M.
    A novel series of semi-synthetic trioxaquines and synthetic trioxolaquines were prepared, in moderate to good yields. Antimalarial activity was evaluated against both the chloroquine-sensitive 3D7 and resistant K1 strain of Plasmodium falciparum and both series of compounds were shown to be active in the low nanomolar range. For comparison the corresponding 9-amino acridine analogues were also prepared and shown to have low nanomolar activity like their quinoline counterparts.
    2009Journal article Restricted access Show more