Endoperoxide carbonyl falcipain 2/3 inhibitor hybrids: toward combination chemotherapy of malaria through a single chemical entity

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.

URI

http://hdl.handle.net/10400.1/4219

Citation

Gibbons, Peter; Verissimo, Edite; Araujo, Nuna C.; Barton, Victoria; Nixon, Gemma L.; Amewu, Richard K.; Chadwick, James; Stocks, Paul A.; Biagini, Giancarlo A.; Srivastava, Abhishek; Rosenthal, Philip J.; Gut, Jiri; Guedes, Rita C.; Moreira, Rui; Sharma, Raman; Berry, Neil; Cristiano, M. Lurdes S.; Shone, Alison E.; Ward, Stephen A.; O’Neill, Paul M. Endoperoxide Carbonyl Falcipain 2/3 Inhibitor Hybrids: Toward Combination Chemotherapy of Malaria through a Single Chemical Entity, Journal of Medicinal Chemistry, 53, 22, 8202-8206, 2010.