Thiazole-substituted benzenesulfonamides as inhibitors of 12 human carbonic anhydrases

Bioorg Chem. 2018 Apr:77:534-541. doi: 10.1016/j.bioorg.2018.02.004. Epub 2018 Feb 10.

Abstract

Four series of para or meta - substituted thiazolylbenzenesulfonamides bearing Cl substituents were designed, synthesized, and evaluated as inhibitors of all 12 catalytically active recombinant human carbonic anhydrase (CA) isoforms. Observed affinities were determined by the fluorescent thermal shift assay and the intrinsic affinities were calculated based on the fractions of binding-ready deprotonated sulfonamide and CA bearing protonated hydroxide bound to the catalytic Zn(II) in the active site. Several compounds exhibited selectivity towards CA IX, an anticancer target. Intrinsic affinities reached 30 pM, while the observed affinities - 70 nM. The structure-intrinsic affinity relationship map of the compounds showed the energetic contributions of the thiazole ring and its substituents.

Keywords: Fluorescent thermal shift assay; Sulfonamide; ThermoFluor®; Thiazole.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Benzenesulfonamides
  • Biocatalysis
  • Carbonic Anhydrase Inhibitors / chemical synthesis
  • Carbonic Anhydrase Inhibitors / chemistry
  • Carbonic Anhydrase Inhibitors / pharmacology*
  • Carbonic Anhydrases / metabolism*
  • Catalytic Domain / drug effects
  • Dose-Response Relationship, Drug
  • Drug Design
  • Humans
  • Isoenzymes / antagonists & inhibitors
  • Isoenzymes / metabolism
  • Molecular Structure
  • Structure-Activity Relationship
  • Sulfonamides / chemical synthesis
  • Sulfonamides / chemistry
  • Sulfonamides / pharmacology*
  • Thermodynamics
  • Thiazoles / chemistry
  • Thiazoles / pharmacology*

Substances

  • Carbonic Anhydrase Inhibitors
  • Isoenzymes
  • Sulfonamides
  • Thiazoles
  • Carbonic Anhydrases