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.

"One-Pot" Synthesis and Antimalarial Activity of Formamidine Derivatives of 4-Anilinoquinoline.

“…Therefore it proved to be more active than 4Ј-dehydroxyfluoro AQ which displayed a 2-fold increase in IC 50 values when compared with AQ against both CQ-sensitive and -resistant strains. 9) In the 4Ј-dehydroxyfluoro AQ, the lack of the hydrogen bond, which is present in AQ between the phenol group and the diethylamino moiety, was responsible for the decreased activity. In compound 7, this phenomenon is balanced by an additional amino moiety.…”

“…The formation of these reactive species in vivo and their binding to cellular proteins and lipids could affect cell function either directly or by immune response. [6][7][8] A 4Ј-dehydroxyfluoro AQ derivative has been reported 9) and proved not to give a quinoneimine by simple oxidation. This was reflected in its high oxidation potential and no bioactivation.…”

Science, medicine and clinical pharmacology. The Lilly Lecture 1994.

“…Most cases of haematological toxicity or hepatotoxicity following amodiaquine administration have occurred in patients taking the drug for prophylaxis, rather than for therapy of acute malaria where the exposure is shorter. The Liverpool group has now shown that by appropriate fluorine substitution it is possible to alter the chemistry of the amodiaquine molecule, allowing retention of its pharmacological antimalarial action yet changing its pattern of metabolism so that only inactive and not reactive metabolites are formed [40]. Whether this will result in the development of an effective antimalarial agent is under investigation.…”

Antimalarial benzoheterocyclic 4-aminoquinolines: Structure–activity relationship, in vivo evaluation, mechanistic and bioactivation studies

“…11, 13 Miroshnikova and coworkers synthesized various isotebuquine analogs (6) with excellent antimalarial activity but poor oral bioavailability. 14 The most successful campaign towards circumventing amodiaquine bioactivation was the synthesis of isoquine (7) and its analogues by O'Neill and co-workers.…”

“…In a previous paper, we reported for the first time the synthesis and potent antiplasmodial activity of benzothiazolyl (9)(10)(11)(12)(13), benzimidazolyl (14)(15)(16)(17), benzoxazolyl (18)(19) and pyridyl (20)(21) analogues of amodiaquine (figure 3) designed to prevent bioactivation to both the quinone imine and aldehyde metabolites. 19 The present paper reports on the bioactivation studies on these compounds and the selection, expanded synthesis and structure activity relationship (SAR) studies of the benzoxazole analogues.…”