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.
Assuntos
Química Farmacêutica/métodos , Cisteína Endopeptidases/química , Inibidores de Cisteína Proteinase/síntese química , Inibidores de Cisteína Proteinase/farmacologia , Piridonas/química , Animais , Antimaláricos/farmacologia , Desenho de Fármacos , Humanos , Concentração Inibidora 50 , Malária/tratamento farmacológico , Modelos Químicos , Conformação Molecular , Plasmodium falciparum/metabolismo , Relação Estrutura-AtividadeRESUMO
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.
