Ligand-based discovery of N-(1,3-dioxo-1H,3H-benzo[de]isochromen-5-yl)-carboxamide and sulfonamide derivatives as thymidylate synthase A inhibitors

Bioorg Med Chem Lett. 2013 Feb 1;23(3):663-8. doi: 10.1016/j.bmcl.2012.11.117. Epub 2012 Dec 7.

Abstract

Phenolnaphthalein derivatives show potential for pharmacological activity as inhibitors of thymidylate synthase (TS) but difficulties in their synthesis and derivatization hinder their development. A deconstruction approach aimed at identifying a suitable new scaffold was proposed. A new scaffold was identified and two compound libraries based on this scaffold were designed. The carboxamide library (Library B) showed specific inhibition activity against Escherichia coli TS, whereas the sulfonamide library (Library C) showed a non-specific inhibition profile against hTS. N-(1,3-Dioxo-1H,3H-benzo[de]isochromen-5-yl)-sulfonamide derivatives, 1C and 9C, showed one order of magnitude improvement in inhibition constant against hTS with respect to the starting lead and represent potential compounds for further lead development.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amides / chemical synthesis*
  • Amides / chemistry
  • Amides / pharmacology
  • Carboxylic Acids / chemical synthesis*
  • Carboxylic Acids / chemistry
  • Carboxylic Acids / pharmacology
  • Drug Discovery*
  • Enzyme Activation / drug effects
  • Escherichia coli / drug effects*
  • Humans
  • Ligands
  • Small Molecule Libraries / chemistry*
  • Small Molecule Libraries / pharmacology
  • Sulfonamides / chemical synthesis*
  • Sulfonamides / chemistry
  • Thymidylate Synthase / antagonists & inhibitors*

Substances

  • Amides
  • Carboxylic Acids
  • Ligands
  • Small Molecule Libraries
  • Sulfonamides
  • Thymidylate Synthase