THE SYNTHESIS AND EVALUATION OF AMODIAQUINE ANALOGUES AS POTENTIAL ANTIMALARIALS

Abstract

The objective of this study is to synthesize and evaluate a number of novel compounds modelled after an established antimalarial agent, amodiaquine (I)(Chart 1, p.J). Amodiaquine is known to intercalate with deoxyribo­ nucleic acid (DNA). Modification of its anilinoquinoline ring system may affect DNA binding and possibly affect its antimalarial activity. Alternatively, ring modification as well as side chain variation will affect the physicochemical properties of the drug, leading to changes in its biological activity.

Chemical Studies In this project, 3 series of amodiaquine analogues have been designed and synthesized (Chart 1, p.3). They are, namely, ( i) the conformationally flexible 7-chloro-4-(4'- methoxy-3-substituted)anilinoquinoline series (IIa-d), (ii) the rigid and planar indolo[J,2-d]quinoline series (IIIa-d), and (iii) the semi-rigid and semi-planar tetrahydroindolo­ benzazepine series (IVa-d).

Compounds with the same side chain, namely, a, hydrogen: b, diethylaminomethyl: c, 3'-dimethylamino­ pyrrolidin-1'-yl-methyl and d, N-3'-dimethylaminopropyl-N­ methylaminomethyl side chains are found in all 3 series.

The structures of these compounds have been confirmed by proton magnetic resonance spectroscopy, mass spectrometry and infra-red spectroscopy as well as elemental analyses.

Physicochemical Studies By means of the solubility method, the negative logarithm of the ionization constants Ka (pKa) of the basic ring nitrogen of IIa, IIIa and IVa were found to be 7.78, 3.99 and 2.62 respectively. The relative basic strength of the ring nitrogens in the different ring systems is discussed.

The logarithm of partition coefficient (log P) of the synthesized compounds was determined by the classical shake flask method. The log P values of Ila, Illa and IVa were found to be 4.94, 4.49, 4.24 respectively. Attempts are made to explain the relative hydrophobicity of the 3 ring systems. The effect of side chain variation on hydrophobicity within each series is also discussed.

Biological studies Preliminary in vitro antimalarial studies against Plasmodium falciparum have been conducted on the series II, III and IV compounds. Antimalarial activities have been shown by compounds with a basic amino side chain, compounds IIb, IId, IIIb and IIIc. This in particular, confirms the importance of the side chain amino group for antimalarial activity. The biological significance of the planarity of the ring system and the distance between the basic ring nitrogen and the side chain nitrogen are discussed.

Additional conclusions on structure-activity relationship can only be drawn from further biological studies.