Tricyclic Sulfonamides Incorporating benzothiopyrano[4,3-c]pyrazole and pyridothiopyrano[4,3-c]pyrazole Effectively Inhibit α- And β-carbonic Anhydrase: X-ray Crystallography and Solution Investigations on 15 Isoforms

J Med Chem. 2012 Nov 26;55(22):9619-29. doi: 10.1021/jm300878g. Epub 2012 Nov 8.

Abstract

Carbonic anhydrases (CAs, EC 4.2.1.1) are ubiquitous isozymes involved in crucial physiological and pathological events, representing the targets of inhibitors with several therapeutic applications. In this connection, we report a new class of carbonic anhydrase inhibitors, based on the thiopyrano-fused pyrazole scaffold to which a pendant 4-sulfamoylphenyl moiety was attached. The new sulfonamides 3a-e were designed as constrained analogues of celecoxib and valdecoxib. The most interesting feature of sulfonamides 3 was their predominantly strong inhibition of human (h) CA I and II, as well as those of the mycobacterial β-class enzymes (Rv1284, Rv3273, and Rv3588c), whereas their inhibitory action against hCA III, IV, VA, VB, VI, VII, IX, XII, XIII, and XIV was found to be at least 2 orders of magnitude lower. X-ray crystallography and structural superposition studies made it possible to explain the very distinct inhibition profile of the tricyclic sulfonamides, different from those of celecoxib and valdecoxib.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carbonic Anhydrase Inhibitors / chemistry
  • Carbonic Anhydrase Inhibitors / pharmacology*
  • Carbonic Anhydrases / chemistry*
  • Catalytic Domain
  • Crystallography, X-Ray
  • Humans
  • Isoenzymes
  • Models, Molecular
  • Molecular Structure
  • Protein Conformation
  • Pyrazoles / chemistry*
  • Structure-Activity Relationship
  • Sulfonamides / chemistry*

Substances

  • Carbonic Anhydrase Inhibitors
  • Isoenzymes
  • Pyrazoles
  • Sulfonamides
  • Carbonic Anhydrases