Sulfonamides incorporating piperazine bioisosteres as potent human carbonic anhydrase I, II, IV and IX inhibitors

Bioorg Chem. 2019 Oct;91:103130. doi: 10.1016/j.bioorg.2019.103130. Epub 2019 Jul 20.

Abstract

Starting from the molecular simplification of (R) 4-(3,4-dibenzylpiperazine-1-carbonyl)benzenesulfonamide 9a, a compound endowed with selectivity for human Carbonic Anhydrase (hCA) IV, a series of piperazines and 4-aminopiperidines carrying a 4-sulfamoylbenzamide moiety as Zn-binding group have been designed and tested on human isoforms hCA I, II, IV and IX, using a stopped flow CO2 hydrase assay. The aim of the work was to derive structure-activity relationships useful for designing isoform selective compounds. These structural modifications changed the selectivity profile of the analogues from hCA IV to hCA I and II, and improved potency. Several of the new compounds showed subnanomolar activity on hCA II. X-ray crystallography of ligand-hCAII complexes was used to compare the binding modes of the new piperazines and the previously synthesized 2-benzyl-piperazine analogues, explaining the inhibition profiles.

Keywords: Carbonic anhydrase; Carbonic anhydrase inhibitors; Isoform selectivity; Piperazine bioisosteres; Piperazines; Sulfonamides.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carbonic Anhydrase Inhibitors / chemical synthesis
  • Carbonic Anhydrase Inhibitors / metabolism
  • Carbonic Anhydrase Inhibitors / pharmacology*
  • Carbonic Anhydrases / chemistry
  • Carbonic Anhydrases / metabolism
  • Catalytic Domain
  • Crystallography, X-Ray
  • Humans
  • Isoenzymes / chemistry
  • Isoenzymes / metabolism
  • Molecular Structure
  • Piperazines / chemical synthesis
  • Piperazines / metabolism
  • Piperazines / pharmacology*
  • Protein Binding
  • Structure-Activity Relationship
  • Sulfonamides / chemical synthesis
  • Sulfonamides / metabolism
  • Sulfonamides / pharmacology*

Substances

  • Carbonic Anhydrase Inhibitors
  • Isoenzymes
  • Piperazines
  • Sulfonamides
  • Carbonic Anhydrases