Synthesis and Antimalarial Screening of Some New Isoquine Analogues

Amodiaquine is a 4-aminoquinoline antimalarial that can cause adverse side effects including hepatic and haematological toxicity. The drug toxicity involves the formation of a reactive metabolite, amodiaquine quinoneimine (AQQI), which binds to cellular macromolecules, leading to hepatotoxicity and agranulocytosis. Interchange of the 3 ́ hydroxyl and the 4 ́ Mannich side-chain function of amodiaquine provide an amodiaquine regioisomer (isoquine) that can not form toxic quinoneimine metabolites. By a simple two-step procedure, four isoquine analogues were synthesized and subsequently evaluated against the chloroquine sensitive RKL-2 strain of Plasmodium falciparum in vitro. All synthesized analogues demonstrated differential level of antimalarial activity against the test strain. However, no compound was found to exhibit better antimalarial property as compared to chloroquine. Key-words: Amodiaquine, isoquine, antimalarial, RKL-2. INTRODUCTION Malaria is the most serious, complex and refractory health problems facing humanity. Almost onehalf of the world’s population is exposed to the threat of malaria and the disease is responsible for two million deaths each year, either directly or in association with acute respiratory infections and anaemia and upto 1 million of those deaths are children. Malaria is a leading cause of morbidity and mortality in developing world 1 . Chloroquine was a mainstream drug in the fight against Plasmodium falciparum, but its efficacy is being eroded by the emergence of resistant parasites. The spread of chloroquine resistance has prompted the re-investigation of the chemistry and pharmacology of alternative antimalarials such as amodiaquine, an other 4aminoquinoline which proved to be effective against chloroquine-resistant strains. 2,3 Amodiaquine is a 4-aminoquinoline antimalarial which is effective against many chloroquine resistant strains of P. falciparum. However, clinical use of amodiaquine has been severely restricted because of associations with hepatotoxicity and agranulocytosis 4,5 . It has been suggested that the toxicity of amodiaquine is related to the reactive electrophillic metabolites formed by oxidation of its phenolic side chian, especially to the formation of a quinineimine by cytochrome P-450catalyzed biological oxidation (Scheme 1). It has been found that amodiaquine is excreted in bile exclusively as the 5 ́ thioether conjugates (glutathione and cysteinyl) in rats 6 . This observation indicates that the parent drug undergoes extensive bioactivation in vivo to form amodiaquine quinoneimine (AQQI) or semiquinoneimine (AQSQI) with subsequent conjugation of glutathione 7 . Scheme 1: Bioactivation of amodiaquine to toxic quinoneimine metabolite by P-450. Structure activity relationship (SAR) studies on amodiaquine had previously shown that wide variations in the side chain can be accommodated with retention of antimalarial activity. Blocking of bioactivation pathways by removal of the phenolic group or introduction of non reactive substituents has been the main strategy. Reducing bioactivation also seems to result in compounds with slower elimination (enhanced biological half life), and increased tissue accumulation 8 . From SAR studies it has been noted that in the amodiaquine and tebuquine series of 4-aminoquinoline analogues, the presence of the 4 ́ hydroxyl group within the aromatic ring imparts greater inherent antimalarial Sanjib Bhattacharya et al /Int.J. ChemTech Res.2009,1(2) 323