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 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.
Gibbons
Peter
P
Department of Chemistry, University of Liverpool, Liverpool, L69 7ZD, UK.
Verissimo
Edite
E
Araujo
Nuna C
NC
Barton
Victoria
V
Nixon
Gemma L
GL
Amewu
Richard K
RK
Chadwick
James
J
Stocks
Paul A
PA
Biagini
Giancarlo A
GA
Srivastava
Abhishek
A
Rosenthal
Philip J
PJ
Gut
Jiri
J
Guedes
Rita C
RC
Moreira
Rui
R
Sharma
Raman
R
Berry
Neil
N
Cristiano
M Lurdes S
ML
Shone
Alison E
AE
Ward
Stephen A
SA
O'Neill
Paul M
PM
D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D047188:Chalcones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004912:Erythrocytes / Q000187:drug effects / Q000469:parasitology; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D010545:Peroxides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010963:Plasmodium falciparum / Q000187:drug effects; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000962:Antimalarials; D047188:Chalcones; D015853:Cysteine Proteinase Inhibitors; D010545:Peroxides; D011355:Prodrugs; D003546:Cysteine Endopeptidases; C416224:falcipain 2; C443101:falcipain 3