“One-Pot” Synthesis and Antimalarial Activity of Formamidine Derivatives of 4-Anilinoquinoline

• Published in: Chemical & pharmaceutical bulletin Vol. 49; no. 8; pp. 933 - 937
• Main Authors: DELARUE, Sandrine, GIRAULT, Sophie, ALI, Fouad DALI, MAES, Louis, GRELLIER, Philippe, SERGHERAERT, Christian
• Format: Journal Article
• Language: English
• Published: TOKYO The Pharmaceutical Society of Japan 01.08.2001; Pharmaceutical Soc Japan; Maruzen
• Subjects: 4-Anilinoquinoline; Amidines - chemical synthesis; Amidines - pharmacology; Amidines - therapeutic use; amodiaquine; Amodiaquine - analogs & derivatives; Amodiaquine - pharmacology; Amodiaquine - therapeutic use; Animals; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antimalarials - chemical synthesis; Antimalarials - pharmacology; Antimalarials - therapeutic use; Antiparasitic agents; Biological and medical sciences; Cell Line; Chemistry; Chemistry, Medicinal; Chemistry, Multidisciplinary; chloroquine; drug design; formamidine; formamidines; Humans; Inhibitory Concentration 50; Life Sciences & Biomedicine; Macrophages - drug effects; malaria; Malaria - drug therapy; Medical sciences; Mice; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Physical Sciences; Plasmodium berghei - drug effects; Plasmodium falciparum; Quinolines - chemical synthesis; Quinolines - pharmacology; Quinolines - therapeutic use; Science & Technology; chloroquine; Plasmodium falciparum; amodiaquine; formamidine; drug design; AMODIAQUINE-INDUCED AGRANULOCYTOSIS; malaria; CHLORDIMEFORM; One pot reaction; Antimalarial; Protozoal disease; Nitrogen heterocycle; Toxicity; Cytotoxicity; Antiprotozoal agent; Plasmodium berghei; Structure activity relation; Chlorine Organic compounds; Parasiticid; Bicyclic compound; Aromatic compound; Chemical synthesis; Human; Protozoa; Apicomplexa; Rodentia; Quinoline derivatives; Parasitosis; In vitro; Infection; In vivo; Vertebrata; Amidine; Chemotherapy; Mammalia; Cell line; Treatment; Mouse; Embryonic cell; Animal; Amodiaquine; Benzenic compound; Macrophage
• ISSN: 0009-2363; 1347-5223
• DOI: 10.1248/cpb.49.933

Amodiaquine (AQ) is an antimalarial which is effective against chloroquino-resistant strains of Plasmodium falciparum but whose clinical use is severely restricted because of associated hepatotoxicity and agranulocytosis. “One-pot” synthesis of formamidines likely to be transformed into AQ derivatives is reported. Compared with AQ, the new compounds were devoid of in vitro cytotoxicity upon human embryonic lung cells and mouse peritoneal macrophages. One showed a potent in vivo activity in mice infected with P. berghei. Transformation of this compound by reductive amination led to a new type of AQ derivatives that displayed an in vitro activity similar to that of AQ but did not lead to toxic quinone-imines.