RESUMO

Acridinediones have previously been shown to have potent antimalarial activity. A series of sulfur isosteres of acridinediones have been synthesized and evaluated for their inhibition of the Plasmodium falciparum cysteine protease falcipain and for their antimalarial activity. A number of these phenothiazines inhibited falcipain and demonstrated activity against cultured P. falciparum parasites at low micromolar concentrations. We propose that the compounds exerted their antimalarial effects by two mechanisms, one of which involves the inhibition of falcipain and a consequent block in parasite degradation of hemoglobin. These compounds and related phenothiazines are worthy of further study as potential antimalarial agents.

Assuntos

Antimaláricos/síntese química , Cisteína Endopeptidases/metabolismo , Inibidores de Cisteína Proteinase/síntese química , Fenotiazinas/química , Plasmodium falciparum/enzimologia , Animais , Antimaláricos/farmacologia , Células Cultivadas , Inibidores de Cisteína Proteinase/farmacologia , Fenotiazinas/farmacologia , Plasmodium falciparum/efeitos dos fármacos