Bile acid derivatives of 5-amino-1,3,4-thiadiazole-2-sulfonamide as new carbonic anhydrase inhibitors: synthesis and investigation of inhibition effects

Bioorg Med Chem. 2002 Aug;10(8):2561-7. doi: 10.1016/s0968-0896(02)00104-9.

Abstract

Bile acid amides (cholan-24-amides) of 5-substituted 1,3,4-thiadiazole-2-sulfonamide have been prepared from lithocholic, deoxycholic, cholic and dehydrocholic acids. Besides, the alcohol functional groups on the cholane ring systems were protected with acetyl group. Amides of the protected cholanes of lithocholic and cholic acids were also synthesized. Later, inhibition effects of these compounds on human carbonic anhydrase isozymes (HCA-I and II) have been investigated in vitro. For the most active compounds, inhibition constants ranged from 66 to 190nM for HCA-II with I(50) (molarity of inhibitor producing a 50% inhibition of CA activity). In addition, in vivo studies were performed for the synthesized compounds in Sprague-Dawley rats. The compounds (11 and 18) showed especially significant inhibition efficacy (p<0.001).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bile Acids and Salts / chemical synthesis*
  • Bile Acids and Salts / pharmacology
  • Carbonic Anhydrase I / antagonists & inhibitors
  • Carbonic Anhydrase II / antagonists & inhibitors
  • Carbonic Anhydrase Inhibitors / administration & dosage
  • Carbonic Anhydrase Inhibitors / chemical synthesis*
  • Carbonic Anhydrase Inhibitors / pharmacology
  • Humans
  • Injections, Intraperitoneal
  • Rats
  • Rats, Sprague-Dawley
  • Structure-Activity Relationship
  • Sulfonamides / chemical synthesis*
  • Sulfonamides / pharmacology
  • Thiadiazoles / chemical synthesis*
  • Thiadiazoles / pharmacology

Substances

  • Bile Acids and Salts
  • Carbonic Anhydrase Inhibitors
  • Sulfonamides
  • Thiadiazoles
  • 5-amino-1,3,4-thiadiazole-2-sulfonamide
  • Carbonic Anhydrase I
  • Carbonic Anhydrase II