Abstract
The synthesis of a series of new isothiazol-3(2H)-one 1,1-dioxides with halogenated (mostly fluorinated) pyridinyl and pentafluorophenyl substituents at 2-position is reported. These compounds (18-24) became easily accessible from 2-thiocyanato-1-carboxaldehydes and aminopyridines, pentafluoroaniline, respectively, by an isothiazolium cyclization-oxidation route. Compound 21 exhibited an IC(50) value of 3.1 microM toward human leukocyte elastase. The proteases cathepsin G, trypsin, cathepsin L, and angiotensin-converting enzyme, and the serine esterases acetylcholinesterase and cholesterol esterase were not inhibited by 21.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acetylcholinesterase / drug effects
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Cathepsin G
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Cathepsin L
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Cathepsins / antagonists & inhibitors
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Crystallography, X-Ray
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Cyclic S-Oxides / chemical synthesis*
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Cyclic S-Oxides / chemistry
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Cyclic S-Oxides / pharmacology*
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Cyclization
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Cysteine Endopeptidases
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Dose-Response Relationship, Drug
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Drug Evaluation, Preclinical
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Enzyme Inhibitors / chemical synthesis*
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology*
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Humans
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Leukocyte Elastase / antagonists & inhibitors*
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Models, Molecular
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Molecular Structure
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Oxidation-Reduction
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Peptidyl-Dipeptidase A / drug effects
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Serine Endopeptidases
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Stereoisomerism
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Sterol Esterase / antagonists & inhibitors
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Structure-Activity Relationship
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Trypsin / drug effects
Substances
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Cyclic S-Oxides
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Enzyme Inhibitors
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Sterol Esterase
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Acetylcholinesterase
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Cathepsins
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ACE protein, human
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Peptidyl-Dipeptidase A
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Serine Endopeptidases
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CTSG protein, human
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Cathepsin G
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Leukocyte Elastase
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Trypsin
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Cysteine Endopeptidases
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CTSL protein, human
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Cathepsin L