RESUMO
A series of etacrynic acid derivatives was synthesized and screened for their in vitro activity against Plasmodium falciparum, as well as their activity against recombinantly expressed falcipain-2 and -3. The two most active compounds of the series displayed IC(50) values of 9.0 and 18.8 microM against Plasmodia.
Assuntos
Antimaláricos/química , Antimaláricos/farmacologia , Cisteína Endopeptidases/efeitos dos fármacos , Inibidores de Cisteína Proteinase/química , Inibidores de Cisteína Proteinase/farmacologia , Ácido Etacrínico/análogos & derivados , Plasmodium falciparum/efeitos dos fármacos , Animais , Antimaláricos/síntese química , Cisteína Endopeptidases/genética , Inibidores de Cisteína Proteinase/síntese química , Estrutura Molecular , Plasmodium falciparum/enzimologia , Proteínas Recombinantes/antagonistas & inibidores , Proteínas Recombinantes/genéticaRESUMO
This paper describes the synthesis of a new class of peptidomimetic cysteine protease inhibitors based on a 1,4-benzodiazepine scaffold and on an electrophilic vinyl sulfone moiety. The former was introduced internally to a peptide sequence that mimics the fragment D-Ser-Gly; the latter was built on the P1-P1' site and reacts as a classical "Michael acceptor", leading to an alkylated enzyme by irreversible addition of the thiol group of the active site cysteine. The introduction of the vinyl sulfone moiety has been accomplished by olefin cross-metathesis, a powerful tool for the formation of carbon-carbon double bonds. New compounds 2-3 have been proven to be potent and selective inhibitors of falcipain-2, a cysteine protease isolated from Plasmodium falciparum, displaying antiplasmodial activity.