Abstract
Four focused libraries targeted for inhibition of the malarial proteases plasmepsin I and II were designed, synthesized, purified, and screened. Selected carboxylic acids and organometallic reactants with diverse physical properties were attached to the hydroxylethylamine scaffold in the P3 and P1' positions to furnish inhibitors with highly improved activity. The concept of controlled and sequential microwave heating was employed for rapid library generation. This combinatorial optimization protocol afforded plasmepsin inhibitors not only with K(i) values in the low nanomolar range, but also with high selectivity versus the human protease cathepsin D. With this class of inhibitory agents, modifications of the P1' substituents resulted in the largest impact on the plasmepsin/cathepsin D selectivity.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Aspartic Acid Endopeptidases / antagonists & inhibitors*
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Biphenyl Compounds / chemistry
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Carboxylic Acids / chemistry
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Cathepsin D / antagonists & inhibitors
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Combinatorial Chemistry Techniques / methods*
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Gas Chromatography-Mass Spectrometry
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Humans
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Magnetic Resonance Spectroscopy
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Microwaves
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Peptide Library
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Plasmodium falciparum / drug effects
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Plasmodium falciparum / enzymology
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Protease Inhibitors / chemical synthesis*
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Protease Inhibitors / chemistry
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Protease Inhibitors / pharmacology*
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Protozoan Proteins
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Pyridines / chemistry
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Structure-Activity Relationship
Substances
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Biphenyl Compounds
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Carboxylic Acids
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Peptide Library
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Protease Inhibitors
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Protozoan Proteins
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Pyridines
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Aspartic Acid Endopeptidases
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plasmepsin
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plasmepsin II
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Cathepsin D