Incorporation of an intramolecular hydrogen-bonding motif in the side chain of 4-aminoquinolines enhances activity against drug-resistant P. falciparum

Abstract

Previous data showing that several chloroquine analogues containing an intramolecular hydrogen-bonding motif were potent against multidrug-resistant P. falciparum led to the exploration of the importance of this motif. A series of 116 compounds containing four different alkyl linkers and various aromatic substitutions with hydrogen bond accepting capability was synthesized. The series showed broad potency against the drug-resistant W2 strain of P. falciparum. In particular, a novel series containing variations of the alpha-aminocresol motif gave eight compounds with IC50 values more potent than 5 nM against the W2 strain. Such simple modifications, significantly altering the pKa and sterics of the basic side chain in chloroquine analogues, may prove to be part of a strategy for overcoming the problem of worldwide resistance to affordable antimalarial drugs.

Figure 1

Structures of α-aminocresol antimalarial compounds and the drug amodiaquine.

Figure 2

Examples of intramolecular hydrogen bonding in antimalarials active against drug-resistant P. falciparum. Amodiaquine, mefloquine and halofantrine are approved drugs used to treat drug-resistant malaria and quinolines 6 and 7 were recently reported to have potent activity against drug-resistant P. falciparum.

Scheme 1

Synthesis of side-chain modified 4-aminoquinolines.

Figure 3

Aldehyde diversity elements used for side chain nitrogen substitutions.

Figure 4

Activity screening data for all compounds against the 3D7 (CQ-sensitive) and W2 (CQ-resistant) parasite strains.