Benzimidazole design, synthesis, and docking to build selective carbonic anhydrase VA inhibitors

Bioorg Med Chem. 2018 Feb 1;26(3):675-687. doi: 10.1016/j.bmc.2017.12.035. Epub 2017 Dec 24.

Abstract

The similarity of human carbonic anhydrase (CA) active sites makes it difficult to design selective inhibitors for one or several CA isoforms that are drug targets. Here we synthesize a series of compounds that are based on 5-[2-(benzimidazol-1-yl)acetyl]-2-chloro-benzenesulfonamide (1a) which demonstrated picomolar binding affinity and significant selectivity for CA isoform five A (VA), and explain the structural influence of inhibitor functional groups to the binding affinity and selectivity. A series of chloro-substituted benzenesulfonamides bearing a heterocyclic tail, together with molecular docking, was used to build inhibitors that explore substituent influence on the binding affinity to the CA VA isoform.

Keywords: 3,4-Dihydro-2H-quinoline; CA inhibitor; Carbonic anhydrase isozyme I, II, III, IV, VA, VB, VI, VII, IX, XII, XIII, and XIV; Docking; Fluorescent thermal shift assay; Imidazole; Indoline; N-Alkylated benzimidazole; Sulfonamide; ThermoFluor®.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Benzimidazoles / chemical synthesis
  • Benzimidazoles / chemistry*
  • Benzimidazoles / metabolism
  • Binding Sites
  • Carbonic Anhydrase Inhibitors / chemical synthesis*
  • Carbonic Anhydrase Inhibitors / chemistry
  • Carbonic Anhydrase Inhibitors / metabolism
  • Carbonic Anhydrases / chemistry*
  • Carbonic Anhydrases / metabolism
  • Catalytic Domain
  • Drug Design*
  • Humans
  • Isoenzymes / antagonists & inhibitors
  • Isoenzymes / metabolism
  • Molecular Docking Simulation
  • Structure-Activity Relationship

Substances

  • Benzimidazoles
  • Carbonic Anhydrase Inhibitors
  • Isoenzymes
  • benzimidazole
  • Carbonic Anhydrases