Synthesis And Evaluation of ۴-Fleuroamodiaquine, A Novel Antimalarial Drug Against Sensitive and Resistant Strains of Plasmodium Falciparum

Background and Objective: Resistance to chloroquine (CQ) in Plasmodium falciparum malaria has become a major health concern in the developing countries. This problem has prompted investigators for finding alternative antimalarials that may be effective against resistant strains. Amodiaquine (AQ) is an antimalarial which is effective against many chloroquine-resistant strains of P. falciparum. However, clinical use of AQ has severely been restricted because of its hepatotoxicity and agranulocytosis side effects. The aim of this study was to design and examine the effects of new analogues of amodiaquine. Materials and Methods: A successful four-step synthesis of a new series of ۴-fluoro analogues was designed and applied to the synthesis of an array of ۱۰ analogues. Antimalarial activity of these agents was assessed against chloroquine-resistant (TM۶) and sensitive strains (۳D۷) of P. falciparum. Results: Several analogues have shown potent antimalarial activity against sensitive ۳D۷ strain of the parasite. The ۶h analogue was superior to the pyrollidino analogue ۶b against all of the strains examined. The N-tert butyl analogue ۶b was potent against chloroquine resistant strains, though it was not quite as active as amodiaquine (AQ) against both chloroquine sensitive and resistant parasites. Conclusion: From the different analogues made, it was shown that the analogue ۶h was more potent than the others. However, this analogue has equal or slightly less potent than amodiaquine and chloroquine against P. falciparum. Further studies on the metabolism and pharmacokinetics of ۶h are recommended.

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Key words: Chloroquine ، Amodiaquine ، Analogues ، Plasmodium falciparum ، Antimalarial activity