Synthesis of a bromotyrosine-derived natural product inhibitor of mycothiol-S-conjugate amidase

Bioorg Med Chem Lett. 2004 Jul 16;14(14):3785-8. doi: 10.1016/j.bmcl.2004.04.095.

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

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Alkylation
  • Amidohydrolases / antagonists & inhibitors*
  • Amidohydrolases / metabolism
  • Anti-Infective Agents / chemical synthesis*
  • Anti-Infective Agents / pharmacology
  • Bacterial Proteins
  • Hydrocarbons, Fluorinated / chemistry
  • Hydrolysis
  • Inhibitory Concentration 50
  • Kinetics
  • Mycobacterium tuberculosis / drug effects*
  • Mycobacterium tuberculosis / enzymology
  • Oxazoles / chemistry
  • Oximes / chemistry
  • Structure-Activity Relationship
  • Tyrosine / analogs & derivatives*
  • Tyrosine / chemical synthesis*
  • Tyrosine / pharmacology

Substances

  • Anti-Infective Agents
  • Bacterial Proteins
  • Hydrocarbons, Fluorinated
  • Oxazoles
  • Oximes
  • bromotyrosine
  • Tyrosine
  • Amidohydrolases
  • N-acetyl-1-D-inosityl-2-amino-2-deoxy-alpha-D-glucopyranoside deacetylase
  • mycothiol S-conjugate amidase