Browsing by Author "Rosenthal, Philip J."
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- Design and synthesis of novel 2-pyridone peptidomimetic falcipain 2/3 inhibitorsPublication . Verissimo, Edite; Berry, Neil; Gibbons, Peter D.; Cristiano, Maria Lurdes Santos; Rosenthal, Philip J.; Gut, Jiri; Ward, Stephen A.; O'Neill, Paul M.The structure-based design, chemical synthesis and in vitro activity evaluation of various falcipain inhibitors derived from 2-pyridone are reported. These compounds contain a peptidomimetic binding determinant and a Michael acceptor terminal moiety capable of deactivating the cysteine protease active site.
- Endoperoxide carbonyl falcipain 2/3 inhibitor hybrids: toward combination chemotherapy of malaria through a single chemical entityPublication . 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.