Synthesis and evaluation of 4fluoro-amodiaquine a novel antimalarial drug against sensitive and resistant strains of Plasmodium falciparum

Abstract number: O48

Asadollahy E., O'Neill P.

Objectives: Resistance to chloroquine (CQ) in Plasmodium falciparum malaria has become a major health concern of the developing world. This resistance has prompted a re-examination of the pharmacology of alternative antimalarials that may be effective against resistant strains. Amodiaquine (AQ) is a 4-aminoquinoline antimalarial which is effective against many chloroquine-resistant strains of P. falciparum. However, clinical use of AQ has been severely restricted because of associations with hepatotoxicity and agranulocytosis. Based on a knowledge of the metabolic basis of amodiaquine toxicity, the aim of this study was to examine the effects of replacing the 4'OH function of amodiaquine with fluorine.

Materials and Methods: A successful four-step synthesis of a new series of 4'-fluoro analogues has been designed and applied to the synthesis of an array of 10 analogues. Malaria parasites were maintained in continuous culture using the method of Jensen and Trager. Antimalarial activity was assessed with an adaption of the 48-h sensitivity assay of Desjardins et al.. using [3H]-hypoxanthine incorporation as an assessment of parasite growth.

Results: The chemistry in the 4'fluoro series provided the target compounds in higher overall yields. Initial testing on both series of analogues was carried out on a chloroquine sensitive (3D7) and resistant strains TM6, K1, TM4, V1S and J164 at the Liverpool School of Tropical. It is apparent that several analogues have potent antimalarial activity against sensitive 3D7 strain of the parasite. The data indicates that 6 h is superior to the pyrollidino analogue 6b against all of the strains examined. It is also clear that N-tert butyl analogue 6b is potent against chloroquine resistant strains, though it is not quite as active as amodiaquine (AQ) against both chloroquine senstitive and resistant parasites.

Conclusion: In summary, work conducted in this study has identified several potent back-up compounds to the clinical candidate. It is clear that the 4'fluoro series has several members with potent activity compared to amodiaquine. It has been shown that (6 h) has is slightly less potent than amodiaquine, chloroquine and the clinical candidate (4b). Further studies on the metabolism and pharmacokinetics of 6 h are necessary.

Session Details

Date: 10/04/2010
Time: 00:00-00:00
Session name: Abstracts 20th European Congress of Clinical Microbiology and Infectious Diseases
Location: Vienna, Austria, 10 - 13 April 2010
Presentation type:
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