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

Journal Article

TítuloEndoperoxide carbonyl falcipain 2/3 inhibitor hybrids: toward combination chemotherapy of malaria through a single chemical entity.
Publication TypeJournal Article
AuthorsGibbons, 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 Publication2010
JournalJ Med Chem
Volume53
Questão22
Date Published2010 Nov 25
Pagination8202-6
ISSN1520-4804
Palavras-chaveAntimalarials, 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.

DOI10.1021/jm1009567
Sapientia

http://www.ncbi.nlm.nih.gov/pubmed/20979352?dopt=Abstract

Alternate JournalJ. Med. Chem.
PubMed ID20979352
Grant ListBB/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