Incorporation of an Intramolecular Hydrogen-Bonding Motif in the Side Chain of 4-Aminoquinolines Enhances Activity against Drug-Resistant P. f alciparum

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 α-aminocresol motif gave eight compounds with IC50 values more potent than 5 nM against the W2 strain. Such simple modifications, significantly altering the pK a 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.