Carbonic anhydrase inhibitors. Synthesis, molecular structures, and inhibition of the human cytosolic isozymes I and II and transmembrane isozymes IX, XII (cancer-associated) and XIV with novel 3-pyridinesulfonamide derivatives

Eur J Med Chem. 2011 Sep;46(9):4403-10. doi: 10.1016/j.ejmech.2011.07.011. Epub 2011 Jul 8.

Abstract

A series of novel 3-pyridinesulfonamide derivatives (2-5, 9-11 and 13-15) have been synthesized and investigated as inhibitors of five isoforms of zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1), that is, the cytosolic ubiquitous CA I and II, and isozymes CA IX and XII (cancer-associated), and XIV. Against the human isozyme hCA I the new compounds showed K(I)s in the range of 0.089-251 μM, whereas toward hCA II, K(I)s = 50.5-487 nM. Isozyme hCA IX was inhibited with K(I)s in the range of 5.2-18.3 nM, while hCA XII with K(I)s = 6.0-16.4 nM, and hCA XIV with K(I)s = 76.4-152.0 nM. All of the new compounds 2-5, 9-11 and 13-15 showed excellent hCA IX inhibitory efficacy, with K(I)s = 5.2-18.3 nM, being much more effective as compared to the clinically used AAZ, MZA, EZA, DCP and IND (K(I)s = 24-50 nM).

MeSH terms

  • Carbonic Anhydrase Inhibitors / chemical synthesis*
  • Carbonic Anhydrase Inhibitors / chemistry
  • Carbonic Anhydrase Inhibitors / pharmacology*
  • Cytosol / enzymology
  • Humans
  • Isoenzymes / antagonists & inhibitors*
  • Magnetic Resonance Spectroscopy
  • Models, Molecular
  • Sulfonamides / chemical synthesis*
  • Sulfonamides / chemistry
  • Sulfonamides / pharmacology*

Substances

  • Carbonic Anhydrase Inhibitors
  • Isoenzymes
  • Sulfonamides