Protein Farnesyltransferase Inhibitors Exhibit Potent Antimalarial Activity

• Published in: Journal of medicinal chemistry Vol. 48; no. 11; pp. 3704 - 3713
• Main Authors: Nallan, Laxman, Bauer, Kevin D, Bendale, Pravin, Rivas, Kasey, Yokoyama, Kohei, Hornéy, Carolyn P, Pendyala, Prakash Rao, Floyd, David, Lombardo, Louis J, Williams, David K, Hamilton, Andrew, Sebti, Said, Windsor, William T, Weber, Patricia C, Buckner, Frederick S, Chakrabarti, Debopam, Gelb, Michael H, Van Voorhis, Wesley C
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 02.06.2005; Amer Chemical Soc
• Subjects: Alkyl and Aryl Transferases - antagonists & inhibitors; Animals; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antimalarials - chemical synthesis; Antimalarials - chemistry; Antimalarials - pharmacology; Antiparasitic agents; Biological and medical sciences; Cells, Cultured; Chemistry, Medicinal; Electrophoresis, Polyacrylamide Gel; Erythrocytes - drug effects; Erythrocytes - parasitology; Farnesyltranstransferase; Female; Humans; Life Sciences & Biomedicine; Malaria - drug therapy; Medical sciences; Mice; Mice, Inbred BALB C; Microscopy, Fluorescence; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Plasmodium berghei; Plasmodium falciparum; Plasmodium falciparum - drug effects; Plasmodium falciparum - enzymology; Plasmodium falciparum - growth & development; Protein Prenylation; Quinolones - chemical synthesis; Quinolones - chemistry; Quinolones - pharmacology; Rats; Science & Technology; Structure-Activity Relationship; IN-VITRO; DESIGN; VIVO; PLASMODIUM-FALCIPARUM; PRENYLATION; MALARIA PARASITES; CULTURE; DISCOVERY; Antimalarial; Imidazole derivatives; Protozoal disease; Five membered ring; Intraperitoneal administration; Nitrile; Nitrogen heterocycle; Farnesyl-diphosphate farnesyltransferase; Antiprotozoal agent; Plasmodium falciparum; Plasmodium berghei; Aminoester; Structure activity relation; Bicyclic compound; Aromatic compound; Chemical synthesis; Protozoa; Apicomplexa; Malaria; Enzyme; Transferases; Rodentia; Enzyme inhibitor; Quinoline derivatives; Parasitosis; In vitro; Infection; In vivo; α-Aminoacid; Vertebrata; Chemotherapy; Mammalia; Treatment; Mouse; Animal; Parasiticide
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm0491039

New therapeutics to combat malaria are desperately needed. Here we show that the enzyme protein farnesyltransferase (PFT) from the malaria parasite Plasmodium falciparum (P. falciparum) is an ideal drug target. PFT inhibitors (PFTIs) are well tolerated in man, but are highly cytotoxic to P. falciparum. Because of their anticancer properties, PFTIs comprise a highly developed class of compounds. PFTIs are ideal for the rapid development of antimalarials, allowing “piggy-backing” on previously garnered information. Low nanomolar concentrations of tetrahydroquinoline (THQ)-based PFTIs inhibit P. falciparum PFT and are cytotoxic to cultured parasites. Biochemical studies suggest inhibition of parasite PFT as the mode of THQ cytotoxicity. Studies with malaria-infected mice show that THQ PFTIs dramatically reduce parasitemia and lead to parasite eradication in the majority of animals. These studies validate P. falciparum PFT as a target for the development of antimalarials and describe a potent new class of THQ PFTIs with antimalaria activity.