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.
Subject(s)
Antimalarials/chemical synthesis , Chalcones/chemical synthesis , Cysteine Endopeptidases/metabolism , Cysteine Proteinase Inhibitors/chemical synthesis , Peroxides/chemical synthesis , Prodrugs/chemical synthesis , Antimalarials/chemistry , Antimalarials/pharmacology , Chalcones/chemistry , Chalcones/pharmacology , Cysteine Proteinase Inhibitors/chemistry , Cysteine Proteinase Inhibitors/pharmacology , Erythrocytes/drug effects , Erythrocytes/parasitology , Inhibitory Concentration 50 , Models, Molecular , Peroxides/chemistry , Peroxides/pharmacology , Plasmodium falciparum/drug effects , Prodrugs/chemistry , Prodrugs/pharmacology , Structure-Activity RelationshipABSTRACT
The structure-based design, chemical synthesis and in vitro activity evaluation of various falcipain inhibitors derived from 2-pyridone are reported. These compounds contain a peptidomimetic binding determinant and a Michael acceptor terminal moiety capable of deactivating the cysteine protease active site.
Subject(s)
Chemistry, Pharmaceutical/methods , Cysteine Endopeptidases/chemistry , Cysteine Proteinase Inhibitors/chemical synthesis , Cysteine Proteinase Inhibitors/pharmacology , Pyridones/chemistry , Animals , Antimalarials/pharmacology , Drug Design , Humans , Inhibitory Concentration 50 , Malaria/drug therapy , Models, Chemical , Molecular Conformation , Plasmodium falciparum/metabolism , Structure-Activity RelationshipABSTRACT
A Diels-Alder/thiol-olefin co-oxygenation approach to the synthesis of novel bicyclic endoperoxides 17a-22b is reported. Some of these endoperoxides (e.g., 17b, 19b, 22a and 22b) have potent nanomolar in vitro antimalarial activity equivalent to that of the synthetic antimalarial agent arteflene. Iron(II)-mediated degradation of sulfone-endoperoxide 19b and spin-trapping with TEMPO provide a spin-trapped adduct 25 indicative of the formation of a secondary carbon centered radical species 24. Reactive C-radical intermediates of this type may be involved in the expression of the antimalarial effect of these bicyclic endoperoxides.
