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

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 aro...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2006-07, Vol.49 (15), p.4535-4543
Main Authors: MADRID, Peter B., LIOU, Ally P., DERISI, Joseph L., GUY, R. Kiplin
Format: Article
Language:English
Subjects:
Aminoquinolines - chemical synthesis
Aminoquinolines - chemistry
Aminoquinolines - pharmacology
Animals
Antibiotics. Antiinfectious agents. Antiparasitic agents
Antimalarials - chemical synthesis
Antimalarials - chemistry
Antimalarials - pharmacology
Antiparasitic agents
Biological and medical sciences
Combinatorial Chemistry Techniques
Drug Resistance
Hydrogen Bonding
Medical sciences
Pharmacology. Drug treatments
Plasmodium falciparum - drug effects
Structure-Activity Relationship
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Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm0600951