RESUMEN
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.
Asunto(s)
Antimaláricos/síntesis química , Chalconas/síntesis química , Cisteína Endopeptidasas/metabolismo , Inhibidores de Cisteína Proteinasa/síntesis química , Peróxidos/síntesis química , Profármacos/síntesis química , Antimaláricos/química , Antimaláricos/farmacología , Chalconas/química , Chalconas/farmacología , Inhibidores de Cisteína Proteinasa/química , Inhibidores de Cisteína Proteinasa/farmacología , Eritrocitos/efectos de los fármacos , Eritrocitos/parasitología , Concentración 50 Inhibidora , Modelos Moleculares , Peróxidos/química , Peróxidos/farmacología , Plasmodium falciparum/efectos de los fármacos , Profármacos/química , Profármacos/farmacología , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Química Farmacéutica/métodos , Cisteína Endopeptidasas/química , Inhibidores de Cisteína Proteinasa/síntesis química , Inhibidores de Cisteína Proteinasa/farmacología , Piridonas/química , Animales , Antimaláricos/farmacología , Diseño de Fármacos , Humanos , Concentración 50 Inhibidora , Malaria/tratamiento farmacológico , Modelos Químicos , Conformación Molecular , Plasmodium falciparum/metabolismo , Relación Estructura-ActividadRESUMEN
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.