Abstract
Despite recent progress in the fight against malaria, the emergence and spread of drug-resistant parasites remains a serious obstacle to the treatment of infections. We recently reported the development of a novel antimalarial drug that combines the 4-aminoquinoline pharmacophore of chloroquine with that of clotrimazole-based antimalarials. Here we describe the optimization of this class of hybrid drug through in-depth structure-activity relationship studies. Antiplasmodial properties and mode of action were characterized in vitro and in vivo, and interactions with the parasite's 'chloroquine resistance transporter' were investigated in a Xenopus laevis oocyte expression system. These tests indicated that piperazine derivatives 4b and 4d may be suitable for coadministration with chloroquine against chloroquine-resistant parasites. The potential for metabolism of the drugs by cytochrome P450 was determined in silico, and the lead compounds were tested for toxicity and mutagenicity. A preliminary pharmacokinetic analysis undertaken in mice indicated that compound 4b has an optimal half-life.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Aminoquinolines / chemical synthesis*
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Aminoquinolines / pharmacokinetics
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Aminoquinolines / pharmacology
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Animals
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Antimalarials / chemical synthesis*
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Antimalarials / pharmacokinetics
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Antimalarials / pharmacology
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Biological Transport
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Cell Line
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Chloroquine / pharmacokinetics
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Chloroquine / pharmacology
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Clotrimazole / analogs & derivatives*
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Clotrimazole / chemical synthesis*
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Clotrimazole / pharmacokinetics
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Clotrimazole / pharmacology
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Drug Resistance
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Female
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Half-Life
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Hemeproteins / antagonists & inhibitors
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Hemeproteins / biosynthesis
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Humans
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Malaria / drug therapy
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Malaria / parasitology
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Male
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Membrane Transport Proteins / genetics
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Membrane Transport Proteins / physiology
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Mice
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Models, Molecular
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Mutation
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Oocytes / drug effects
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Oocytes / metabolism
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Piperazines / chemical synthesis
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Piperazines / pharmacokinetics
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Piperazines / pharmacology
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Plasmodium berghei
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Plasmodium falciparum / drug effects
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Protozoan Proteins / genetics
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Protozoan Proteins / physiology
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Rats
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Rats, Sprague-Dawley
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Stereoisomerism
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Structure-Activity Relationship
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Ventricular Pressure / drug effects
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Xenopus laevis
Substances
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Aminoquinolines
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Antimalarials
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Hemeproteins
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Membrane Transport Proteins
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PfCRT protein, Plasmodium falciparum
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Piperazines
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Protozoan Proteins
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hemozoin
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Chloroquine
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Clotrimazole
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4-aminoquinoline