Incorporation of an Intramolecular Hydrogen-bonding Motif in the Side Chain of 4-aminoquinolines Enhances Activity Against Drug-resistant P. Falciparum.
From: Department of Pharmaceutical Chemistry, University of California, San Francisco, California 94143-2280, USA.
Journal of medicinal chemistry
- Publish Date: Jul 2006
- ISSN: 0022-2623
- Volume: 49
- Issue: 15
- Pages: 4535-43
- Medium: Print
- Language: English
- Citation (JAMA): Madrid Peter B, Liou Ally P, DeRisi Joseph L, et al. Incorporation of an Intramolecular Hydrogen-bonding Motif in the Side Chain of 4-aminoquinolines Enhances Activity Against Drug-resistant P. Falciparum.. J. Med. Chem. Jul 2006;49:4535-43
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.
Mesh Headings (Keywords): Aminoquinolines, Animals, Antimalarials, Combinatorial Chemistry Techniques, Drug Resistance, Hydrogen Bonding, Plasmodium falciparum, Structure-Activity Relationship
Check for Full Text / PubMed Unique Identifier (PMID): 16854059
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