SYNTHESIS AND ANTIMALARIAL EFFECTS OF PHENOTHIAZINE INHIBITORS OF A PLASMODIUM-FALCIPARUM CYSTEINE PROTEASE

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