Small Molecule Alkoxy Oriented Selectiveness on Human Carbonic Anhydrase II and IX Inhibition

ChemMedChem. 2022 Jun 3;17(11):e202200148. doi: 10.1002/cmdc.202200148. Epub 2022 Apr 26.

Abstract

We report aryl sulfonamide inhibitors of human carbonic anhydrase (hCA; EC 4.2.1.1) enzymes containing short ureido alkoxy tails. The inhibition potency of such compounds was investigated in vitro on the major hCA isoforms (i.e. I, II, IX, and XII). A selection of the most potent inhibitory derivatives against the hCA IX isoform (i.e. 5a, 5c, and 6c) was studied, and their binding modes on either hCA II and IX-mimic isoform were assessed by X-ray crystallography on the corresponding ligand/protein adducts. This study adds to the field of developing hCA inhibitors at molecular level the critical interactions governing ligand selectivity.

Keywords: Carbonic anhydrase inhibitors (CAIs); Isoform selectivity; Structure-activity relationships (SARs); X-ray crystallography.

MeSH terms

  • Alcohols
  • Antigens, Neoplasm / metabolism
  • Carbonic Anhydrase II* / metabolism
  • Carbonic Anhydrase IX / metabolism
  • Carbonic Anhydrase Inhibitors* / chemistry
  • Humans
  • Isoenzymes / metabolism
  • Ligands
  • Molecular Structure
  • Structure-Activity Relationship

Substances

  • Alcohols
  • Antigens, Neoplasm
  • Carbonic Anhydrase Inhibitors
  • Isoenzymes
  • Ligands
  • alkoxyl radical
  • Carbonic Anhydrase II
  • Carbonic Anhydrase IX