Pyridazinone substituted benzenesulfonamides as potent carbonic anhydrase inhibitors

Bioorg Med Chem Lett. 2016 Feb 15;26(4):1337-41. doi: 10.1016/j.bmcl.2015.12.016. Epub 2015 Dec 7.

Abstract

A series of sulfonamide derivatives (2a-l) incorporating substituted pyridazinone moieties were investigated for the inhibition of two human cytosolic carbonic anhydrase isoforms, hCA I and hCA II. All these compounds, together with the clinically used sulfonamide acetazolamide were investigated as inhibitors of the physiologically relevant isozymes I and II. These sulfonamides showed very strong inhibition against all these isoforms with K(I)'s in the range of 0.98-8.5 nM which makes such molecules possible to be used as leads for discovery of novel effective CA inhibitors targeting other isoforms with medicinal chemistry applications.

Keywords: Enzyme inhibitors; Human carbonic anhydrase; Sulfonamides.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Benzenesulfonamides
  • Carbonic Anhydrase I / antagonists & inhibitors
  • Carbonic Anhydrase I / metabolism
  • Carbonic Anhydrase II / antagonists & inhibitors
  • Carbonic Anhydrase II / metabolism
  • Carbonic Anhydrase Inhibitors / chemical synthesis
  • Carbonic Anhydrase Inhibitors / chemistry*
  • Drug Design
  • Humans
  • Pyridazines / chemistry
  • Structure-Activity Relationship
  • Sulfonamides / chemical synthesis
  • Sulfonamides / chemistry*

Substances

  • Carbonic Anhydrase Inhibitors
  • Pyridazines
  • Sulfonamides
  • Carbonic Anhydrase I
  • Carbonic Anhydrase II