RESUMO
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.
Assuntos
Antimaláricos/síntese química , Chalconas/síntese química , Cisteína Endopeptidases/metabolismo , Inibidores de Cisteína Proteinase/síntese química , Peróxidos/síntese química , Pró-Fármacos/síntese química , Antimaláricos/química , Antimaláricos/farmacologia , Chalconas/química , Chalconas/farmacologia , Inibidores de Cisteína Proteinase/química , Inibidores de Cisteína Proteinase/farmacologia , Eritrócitos/efeitos dos fármacos , Eritrócitos/parasitologia , Concentração Inibidora 50 , Modelos Moleculares , Peróxidos/química , Peróxidos/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Pró-Fármacos/química , Pró-Fármacos/farmacologia , Relação Estrutura-AtividadeRESUMO
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.