Endoperoxide Carbonyl Falcipain 2/3 Inhibitor Hybrids: Toward Combination Chemotherapy of Malaria through a Single Chemical Entity

作者：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 Ludes S; Shone Alison E; Ward Stephen A; O'Neill Paul M^*

来源：Journal of Medicinal Chemistry, 2010, 53(22): 8202-8206.

DOI：10.1021/jm1009567

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 carbonyl-masking 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 eytotoxic 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.

• 出版日期2010-11-25