Parallel solid-phase synthesis and evaluation of inhibitors of Streptomyces coelicolor type II dehydroquinase

J Med Chem. 2003 Dec 18;46(26):5735-44. doi: 10.1021/jm030987q.

Abstract

A series of 1-substituted and 4-substituted benzyl analogues of the known inhibitor (1S,3R,4R)-1,3,4-trihydroxy-5-cyclohexene-1-carboxylic acid has been synthesized and tested as inhibitors of Streptomyces coelicolor type II dehydroquinase. The solid-phase syntheses of 18 new analogues are reported. The most potent inhibitor, 2-nitrobenzyloxy analogue 5i, has K(i) of 8 microM, more than 30 times lower than the K(M) of the substrate and approximately 4 times more potent than the original inhibitor. The binding modes of the synthesized analogues in the active site were studied by molecular docking with GOLD 2.0.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Benzyl Compounds / chemical synthesis*
  • Benzyl Compounds / chemistry
  • Binding Sites
  • Cyclohexanes / chemical synthesis*
  • Cyclohexanes / chemistry
  • Hydro-Lyases / antagonists & inhibitors*
  • Hydro-Lyases / chemistry
  • Models, Molecular
  • Protein Binding
  • Shikimic Acid / analogs & derivatives
  • Shikimic Acid / chemical synthesis*
  • Shikimic Acid / chemistry
  • Spectrophotometry, Ultraviolet
  • Streptomyces / chemistry*
  • Structure-Activity Relationship

Substances

  • 1,3,4-trihydroxy-5-cyclohexene-1-carboxylic acid
  • Benzyl Compounds
  • Cyclohexanes
  • Shikimic Acid
  • Hydro-Lyases
  • 3-dehydroquinate dehydratase