Abstract
Recently we described the structures of two new bromotyrosine-derived alkaloids that inhibit the detoxification enzyme mycothiol-S-conjugate amidase (MCA) from Mycobacterium tuberculosis. Here we describe a concise total synthesis of bromotyrosine oxime 1. The six-step synthesis of 1 utilized a trifluoromethyloxazole intermediate, whose hydrolysis product underwent alkylation and coupling to agmatine to give the inhibitor in approximately 40% overall yield. Oxime 1 inhibited MCA and its homolog AcGI deacetylase with IC(50) values of 30 and 150 microM, respectively.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Alkylation
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Amidohydrolases / antagonists & inhibitors*
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Amidohydrolases / metabolism
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Anti-Infective Agents / chemical synthesis*
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Anti-Infective Agents / pharmacology
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Bacterial Proteins
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Hydrocarbons, Fluorinated / chemistry
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Hydrolysis
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Inhibitory Concentration 50
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Kinetics
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Mycobacterium tuberculosis / drug effects*
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Mycobacterium tuberculosis / enzymology
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Oxazoles / chemistry
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Oximes / chemistry
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Structure-Activity Relationship
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Tyrosine / analogs & derivatives*
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Tyrosine / chemical synthesis*
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Tyrosine / pharmacology
Substances
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Anti-Infective Agents
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Bacterial Proteins
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Hydrocarbons, Fluorinated
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Oxazoles
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Oximes
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bromotyrosine
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Tyrosine
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Amidohydrolases
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N-acetyl-1-D-inosityl-2-amino-2-deoxy-alpha-D-glucopyranoside deacetylase
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mycothiol S-conjugate amidase