title: The effect of fluorine substitution on the metabolism and antimalarial activity of amodiaquine.
abstract: Amodiaquine (AQ) (2) is a 4-aminoquinoline antimalarial which causes adverse side effects such as agranulocytosis and liver damage. The observed drug toxicity is believed to be related to the formation of an electrophilic metabolite, amodiaquine quinone imine (AQQI), which can bind to cellular macro-molecules and initiate hypersensitivity reactions. 5'-Fluoroamodiaquine (5'-FAQ, 3), 5',6'-difluoroamodiaquine (5',6'-DIFAQ,4), 2',6'-difluoroamodiaquine (2',6'-DIFAQ,5), 2',5',6'-trifluoroamodiaquine (2',5',6'-TRIFAQ, 6) and 4'-dehydroxy-4'-fluoroamodiaquine (4'-deOH-4'-FAQ,7) have been synthesized to assess the effect of fluorine substitution on the oxidation potential, metabolism, and in vitro antimalarial activity of amodiaquine. The oxidation potentials were measured by cyclic voltammetry, and it was observed that substitution at the 2',6'- and the 4'-positions (2',6'-DIFAQ and 4'-deOH-4'-FAQ) produced analogues with significantly higher oxidation potentials than the parent drug. Fluorine substitution at the 2',6'-positions and the 4'-position also produced analogues that were more resistant to bioactivation. Thus 2',6'-DIFAQ and 4'-deOH-4'-FAQ produced thioether conjugates corresponding to 2.17% (SD: +/- 0.27%) and 0% of the dose compared with 11.87% (SD: +/- 1.31%) of the dose for amodiaquine. In general the fluorinated analogues had similar in vitro antimalarial activity to amodiaquine against the chloroquine resistant K1 strain of Plasmodium falciparum and the chloroquine sensitive T9-96 strain of P. falciparum with the notable exception of 2',5',6'-TRIFAQ (6). The data presented indicate that fluorine substitution at the 2',6'-positions and replacement of the 4'-hydroxyl of amodiaquine with fluorine produces analogues (5 and 7) that maintain antimalarial efficacy in vitro and are more resistant to oxidation and hence less likely to form toxic quinone imine metabolites in vivo.
authors.affiliation: Department of Organic Chemistry, University of Liverpool, U.K.
authors.forename: P M
authors.initials: PM
authors.lastname: O'Neill
authors.forename: A C
authors.initials: AC
authors.lastname: Harrison
authors.forename: R C
authors.initials: RC
authors.lastname: Storr
authors.forename: S R
authors.initials: SR
authors.lastname: Hawley
authors.forename: S A
authors.initials: SA
authors.lastname: Ward
authors.forename: B K
authors.initials: BK
authors.lastname: Park
mesh_terms: D000655:Amodiaquine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D002738:Chloroquine / Q000494:pharmacology; D005461:Fluorine / Q000737:chemistry*; D015394:Molecular Structure; D010084:Oxidation-Reduction; D010963:Plasmodium falciparum / Q000187:drug effects*; D013329:Structure-Activity Relationship
chemical_list: C087146:2',6'-difluoroamodiaquine; C087147:4'-dehydroxy-4'-fluoroamodiaquine; D000655:Amodiaquine; D005461:Fluorine; D002738:Chloroquine