Abstract
The design of conformationally restricted eight-membered ring diketones as transition state mimics of the mechanism of action of cyclotheonamides on serine proteases is described. Two target compounds are prepared from mutilin, derived from the natural product pleuromutilin. Compound 3 shows significant inhibition of plasmin and urokinase in enzyme rate assays, but an analogue 4 in which the amide moiety has been omitted does not. An X-ray crystal structure of the diketone 3 confirms the conformational predictions made by molecular modelling.
MeSH terms
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Bridged-Ring Compounds / chemical synthesis
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Bridged-Ring Compounds / pharmacology
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Drug Design
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Ketones / chemical synthesis*
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Ketones / chemistry
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Ketones / pharmacology
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Kinetics
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Models, Molecular
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Molecular Conformation
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Molecular Structure
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Polycyclic Compounds / chemistry
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Polycyclic Compounds / pharmacology
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Serine Proteinase Inhibitors / chemical synthesis*
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Serine Proteinase Inhibitors / pharmacology
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Structure-Activity Relationship
Substances
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Bridged-Ring Compounds
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Ketones
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Polycyclic Compounds
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Serine Proteinase Inhibitors
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mutilin