Anticonvulsant 4-aminobenzenesulfonamide derivatives with branched-alkylamide moieties: X-ray crystallography and inhibition studies of human carbonic anhydrase isoforms I, II, VII, and XIV

J Med Chem. 2011 Jun 9;54(11):3977-81. doi: 10.1021/jm200209n. Epub 2011 May 9.

Abstract

Aromatic amides comprising branched aliphatic carboxylic acids and 4-aminobenzenesulfonamide were evaluated for their inhibition of carbonic anhydrase (CA) isoforms. Of the most anticonvulsant-active compounds (2, 4, 13, 16, and 17), only 13, 16, and 17 were potent inhibitors of CAs VII and XIV. Compounds 9, 14, and 19 inhibited CA II, while 10 and 12 inhibited all isoforms. Structural studies suggest that differences in the active sites' hydrophobicity modulate the affinity of the inhibitors.

MeSH terms

  • Anticonvulsants / chemical synthesis
  • Anticonvulsants / chemistry*
  • Anticonvulsants / pharmacology*
  • Binding Sites
  • Carbonic Anhydrase Inhibitors / chemical synthesis
  • Carbonic Anhydrase Inhibitors / chemistry*
  • Carbonic Anhydrase Inhibitors / pharmacology*
  • Carbonic Anhydrases / metabolism
  • Crystallography, X-Ray
  • Epilepsy / drug therapy
  • Humans
  • Hydrophobic and Hydrophilic Interactions
  • Protein Isoforms / chemical synthesis
  • Protein Isoforms / chemistry
  • Protein Isoforms / pharmacology
  • Structure-Activity Relationship
  • Sulfonamides / chemical synthesis
  • Sulfonamides / chemistry*
  • Sulfonamides / pharmacology*

Substances

  • Anticonvulsants
  • Carbonic Anhydrase Inhibitors
  • Protein Isoforms
  • Sulfonamides
  • Carbonic Anhydrases