Handling drug-target selectivity: A study on ureido containing Carbonic Anhydrase inhibitors

Eur J Med Chem. 2021 Feb 15:212:113035. doi: 10.1016/j.ejmech.2020.113035. Epub 2020 Nov 21.

Abstract

Here we report the synthesis of a series of taurine substituted sulfonamide derivatives 1-29 having the ureido moiety installed at the tail section as selective inhibitors of the tumor associated human (h) Carbonic Anhydrase (CA; EC 4.2.1.1) IX and XII. The series was deeply investigated for their kinetic features which demonstrated a strong dependence on the ureido moiety. High resolution X-ray crystallographic investigation on selected ligand adducts complexed with hCA II and hCA IX-mimic revealed a strong correlation between the ureido moiety and the amino acid residues Q92 and Q67 in both the hCA II and hCA IX-mimic, contributing to highly stabilized ligand-protein complex.

Keywords: Carbonic anhydrase IX; Carbonic anhydrase inhibitors (CAIs); Taurine; Ureido.

MeSH terms

  • Carbonic Anhydrase Inhibitors / chemical synthesis
  • Carbonic Anhydrase Inhibitors / chemistry
  • Carbonic Anhydrase Inhibitors / pharmacology*
  • Carbonic Anhydrases / metabolism*
  • Crystallography, X-Ray
  • Dose-Response Relationship, Drug
  • Humans
  • Isoenzymes / antagonists & inhibitors
  • Isoenzymes / metabolism
  • Models, Molecular
  • Molecular Structure
  • Structure-Activity Relationship

Substances

  • Carbonic Anhydrase Inhibitors
  • Isoenzymes
  • Carbonic Anhydrases