66684-68-2Relevant academic research and scientific papers
The Effect of Fluorine Substitution on the Metabolism and Antimalarial Activity of Amodiaquine
O'Neill, Paul M.,Harrison, Anthony C.,Storr, Richard C.,Hawley, Shaun R.,Ward, Stephen A.,Park, B. Kevin
, p. 1362 - 1370 (2007/10/02)
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 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 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 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 2.17percent (SD: +/-0.27percent) and 0percent of the dose compared with 11.87percent (SD: +/-1.31percent) 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.
AROMATIC POLYFLUORO COMPOUNDS LVII . NUCLEOPHILIC REPLACEMENT REACTIONS OF 1,2,3,5-TETRAFLUORO-4-NITROBENZENE, 1,2,3,5-TETRAFLUORODINITROBENZENE AND 1-BROMO-2,3,4,6-TETRAFLUORO-5-NITROBENZENE
Burdon, James,Fisher, Derek,Parsons Ian W.,Tatlow, John Colin
, p. 507 - 514 (2007/10/02)
The title compounds have been treated with dimethylamine and sodium methoxide in polar solvents, and the isomer ratios of the products determined.Although attack para to the nitro group is in each case favoured over ortho, it is so by only surprisingly small factors.Structures have mostly been assigned spectroscopically, supported in one case by a chemical proof.The dinitrotetrafluorobenzene is activated sufficiently to react directly with methanol at 35 deg C, with a pseudo first order rate constant of (7 +/- 1) * 10-5 s-1.
