Journal Article
| Title | Endoperoxide carbonyl falcipain 2/3 inhibitor hybrids: toward combination chemotherapy of malaria through a single chemical entity. |
| Publication Type | Journal Article |
| Authors | Gibbons, P, Verissimo, E, Araujo, NC, Barton, V, Nixon, GL, Amewu, RK, Chadwick, J, Stocks, PA, Biagini, GA, Srivastava, A, Rosenthal, PJ, Gut, J, Guedes, RC, Moreira, R, Sharma, R, Berry, N, Cristiano, MLS, Shone, AE, Ward, SA, O'Neill, PM |
| Year of Publication | 2010 |
| Journal | J Med Chem |
| Volume | 53 |
| Issue | 22 |
| Date Published | 2010 Nov 25 |
| Pagination | 8202-6 |
| ISSN | 1520-4804 |
| Keywords | Antimalarials, Chalcones, Cysteine Endopeptidases, Cysteine Proteinase Inhibitors, Erythrocytes, Inhibitory Concentration 50, Models, Molecular, Peroxides, Plasmodium falciparum, Prodrugs, Structure-Activity Relationship |
| Abstract | 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 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. |
| DOI | 10.1021/jm1009567 |
| Sapientia | |
| Alternate Journal | J. Med. Chem. |
| PubMed ID | 20979352 |
| Grant List | BB/C006321/1 / / Biotechnology and Biological Sciences Research Council / United Kingdom BBS/B/05508 / / Biotechnology and Biological Sciences Research Council / United Kingdom BBS/Q/Q/2004/06032 / / Biotechnology and Biological Sciences Research Council / United Kingdom BBS/S/P/2003/10353 / / Biotechnology and Biological Sciences Research Council / United Kingdom |
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