Microwave assisted synthesis of novel acridine-acetazolamide conjugates and investigation of their inhibition effects on human carbonic anhydrase isoforms hCA I, II, IV and VII

Bioorg Med Chem. 2016 Aug 15;24(16):3548-55. doi: 10.1016/j.bmc.2016.05.064. Epub 2016 May 30.

Abstract

4-Amino-N-(5-sulfamoyl-1,3,4-thiadiazol-2-yl)benzamide was condensed with cyclic-1,3-diketones (dimedone and cyclohexane-1,3-dione) and aromatic aldehydes under microwave irradiation, leading to a series of acridine-acetazolamide conjugates. The new compounds were investigated as inhibitors of carbonic anhydrases (CA, EC 4.2.1.1), and more precisely cytosolic isoforms hCA I, II, VII and membrane-bound one hCA IV. All investigated isoforms were inhibited in low micromolar and nanomolar range by the new compounds. hCA IV and VII were inhibited with KIs in the range of 29.7-708.8nM (hCA IV), and of 1.3-90.7nM (hCA VII). For hCA I and II the KIs were in the range of 6.7-335.2nM (hCA I) and of 0.5-55.4nM (hCA II). The structure-activity relationships (SAR) for the inhibition of these isoforms with the acridine-acetazolamide conjugates reported here were delineated.

Keywords: Acetazolamide; Acridine; Carbonic anhydrase; Enzyme inhibition; Isoforms CA I, II, IV and VII.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetazolamide / chemistry*
  • Acetazolamide / pharmacology*
  • Carbonic Anhydrase Inhibitors / chemistry
  • Carbonic Anhydrase Inhibitors / pharmacology*
  • Humans
  • Isoenzymes / drug effects*
  • Microwaves*
  • Spectrum Analysis / methods

Substances

  • Carbonic Anhydrase Inhibitors
  • Isoenzymes
  • Acetazolamide