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

摘要

Previous data showing that several chloroquine analogs 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 8 compounds with IC50's 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 analogs, may prove to be part of a strategy for overcoming the problem of worldwide resistance to affordable antimalarial drugs.