Benzimidazole derivatives as potent and isoform selective tumor-associated carbonic anhydrase IX/XII inhibitors

Bioorg Chem. 2020 Jan:95:103544. doi: 10.1016/j.bioorg.2019.103544. Epub 2019 Dec 28.

Abstract

We describe the synthesis of a series of 2-arylbenzimidazole derivatives bearing sulfonamide functionality (4a-d, 7a-c and 10) as well as hydroxamic acid (15a-b), carboxylic acid (16a-b), carboxamide (17a-b) and boronic acid (22a-b and 26) functionalities, which act as human carbonic anhydrase (hCA, EC 4.2.1.1) inhibitors. The newly synthesized benzimidazole derivatives were evaluated against 4 physiologically relevant CA isoforms (hCA I, II, IX, and XII), and especially the sulfonamide-containing benzimidazoles demonstrated intriguing inhibitory activity against tumor associated CA IX and XII with KI values in the range of 5.2-29.3 nM and 9.9-41.7 nM, respectively. Notably, compound 4c was the most potent and selective CA IX (KI = 6.6 nM) and XII (KI = 9.9 nM) inhibitor with a significant selectivity ratio over cytosolic CA I and II isoforms in the range of 3.4-25.2. In addition, compounds having hydroxamic acid (15a-b) or carboxylic acid (16a-b) functionalities resulted in greater selectivity ratios for CA IX/XII over CAI/II in the range of 4.1-121.5 although with KI values in lower micromolar potency (KIs = 0.36-0.85 μM for CA IX/XII).

Keywords: Benzimidazole; Carbonic anhydrase; Carboxylic acid; Hydroxamic acid; Sulfonamide.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, Neoplasm / drug effects*
  • Antineoplastic Agents / pharmacology*
  • Benzimidazoles / pharmacology*
  • Carbonic Anhydrase IX / drug effects*
  • Carbonic Anhydrase Inhibitors / pharmacology*
  • Carbonic Anhydrases / drug effects*
  • Humans
  • Spectrum Analysis / methods

Substances

  • Antigens, Neoplasm
  • Antineoplastic Agents
  • Benzimidazoles
  • Carbonic Anhydrase Inhibitors
  • CA9 protein, human
  • Carbonic Anhydrase IX
  • Carbonic Anhydrases
  • carbonic anhydrase XII