Synthesis and Antimalarial Effects of Phenothiazine Inhibitors of a Plasmodium falciparum Cysteine Protease

• Published in: Journal of medicinal chemistry Vol. 40; no. 17; pp. 2726 - 2732
• Main Authors: Domínguez, José N, López, Simón, Charris, Jaime, Iarruso, Lúcido, Lobo, Gricela, Semenov, Andrey, Olson, Jed E, Rosenthal, Philip J
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 15.08.1997; Amer Chemical Soc
• Subjects: Animals; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antimalarials - chemical synthesis; Antimalarials - pharmacology; Antiparasitic agents; Biological and medical sciences; Cells, Cultured; Chemistry, Medicinal; Cysteine Endopeptidases - metabolism; Cysteine Proteinase Inhibitors - chemical synthesis; Cysteine Proteinase Inhibitors - pharmacology; Life Sciences & Biomedicine; Medical sciences; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Phenothiazines - chemistry; Phenothiazines - pharmacology; Plasmodium falciparum - drug effects; Plasmodium falciparum - enzymology; Science & Technology; ACRIDINEDIONE; BLOOD SCHIZONTOCIDAL ACTION; INVITRO; FLOXACRINE; DRUGS; MALARIA; AGENTS; BERGHEI; DERIVATIVES; PROTEINASE; Protozoa; Antimalarial; Sulfur nitrogen heterocycle; Sulfone; Enzyme; Cysteine endopeptidases; Enzyme inhibitor; Phenothiazine derivatives; Tricyclic compound; Peptidases; Plasmodium falciparum; Structure activity relation; Parasiticid; Hydrolases; Aromatic compound; Mechanism of action; Chemical synthesis; Sporozoa; Halogen Organic compounds
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm970266p

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.