Identification of triazinoindol-benzimidazolones as nanomolar inhibitors of the Mycobacterium tuberculosis enzyme TDP-6-deoxy-d-xylo-4-hexopyranosid-4-ulose 3,5-epimerase (RmlC)

Bioorg Med Chem. 2010 Jan 15;18(2):896-908. doi: 10.1016/j.bmc.2009.11.033. Epub 2009 Nov 20.

Abstract

High-throughput screening of 201,368 compounds revealed that 1-(3-(5-ethyl-5H-[1,2,4]triazino[5,6-b]indol-3-ylthio)propyl)-1H-benzo[d]imidazol-2(3H)-one (SID 7975595) inhibited RmlC a TB cell wall biosynthetic enzyme. SID 7975595 acts as a competitive inhibitor of the enzyme's substrate and inhibits RmlC as a fast-on rate, fully reversible inhibitor. An analog of SID 7975595 had a K(i) of 62nM. Computer modeling showed that the binding of the tethered two-ringed system into the active site occurred at the thymidine binding region for one ring system and the sugar region for the other ring system.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Aorta / cytology
  • Aorta / drug effects
  • Benzimidazoles / chemical synthesis
  • Benzimidazoles / chemistry
  • Benzimidazoles / pharmacology*
  • Carbohydrate Epimerases / antagonists & inhibitors*
  • Catalytic Domain
  • Cell Survival / drug effects
  • Computer Simulation
  • Dose-Response Relationship, Drug
  • Endothelial Cells / drug effects
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • High-Throughput Screening Assays
  • Humans
  • Indoles / chemical synthesis
  • Indoles / chemistry
  • Indoles / pharmacology*
  • Models, Chemical
  • Mycobacterium tuberculosis / enzymology*
  • Structure-Activity Relationship

Substances

  • 1-(3-(5-ethyl-5H-(1,2,4)triazino(5,6-b)indol-3-ylthio)propyl)-1H-benzo(d)imidazol-2(3H)-one
  • Benzimidazoles
  • Enzyme Inhibitors
  • Indoles
  • Carbohydrate Epimerases
  • dTDP-4-ketorhamnose 3,5-epimerase