Indapamide-like benzenesulfonamides as inhibitors of carbonic anhydrases I, II, VII, and XIII

Bioorg Med Chem. 2010 Nov 1;18(21):7357-64. doi: 10.1016/j.bmc.2010.09.016. Epub 2010 Sep 15.

Abstract

A series of novel 2-chloro-5-[(1-benzimidazolyl- and 2-benzimidazolylsulfanyl)acetyl]benzene-sulfonamides were designed and synthesized. Their binding to recombinant human carbonic anhydrase (hCA) isozymes I, II, VII, and XIII was determined by isothermal titration calorimetry and thermal shift assay. The designed S-alkylated benzimidazole derivatives exhibited stronger binding than the indapamide-like N-alkylated benzimidazoles, with the K(d) reaching about 50-100 nM with drug-targeted hCAs VII and XIII. The cocrystal structures of selected compounds with hCA II were determined by X-ray crystallography, and structural features of the binding event were revealed.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Carbonic Anhydrase I / antagonists & inhibitors
  • Carbonic Anhydrase I / genetics
  • Carbonic Anhydrase I / metabolism
  • Carbonic Anhydrase II / antagonists & inhibitors
  • Carbonic Anhydrase II / genetics
  • Carbonic Anhydrase II / metabolism
  • Carbonic Anhydrase Inhibitors / chemical synthesis
  • Carbonic Anhydrase Inhibitors / chemistry*
  • Carbonic Anhydrase Inhibitors / pharmacology
  • Carbonic Anhydrases / chemistry*
  • Carbonic Anhydrases / genetics
  • Carbonic Anhydrases / metabolism
  • Crystallography, X-Ray
  • Humans
  • Indapamide / chemistry*
  • Kinetics
  • Protein Binding
  • Protein Structure, Tertiary
  • Recombinant Proteins / antagonists & inhibitors
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Sulfonamides / chemical synthesis
  • Sulfonamides / chemistry*
  • Sulfonamides / pharmacology

Substances

  • Carbonic Anhydrase Inhibitors
  • Recombinant Proteins
  • Sulfonamides
  • benzenesulfonamide
  • Carbonic Anhydrase I
  • Carbonic Anhydrase II
  • CA13 protein, human
  • Carbonic Anhydrases
  • carbonic anhydrase VI
  • Indapamide