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

Uslu A. G., Maz T. G., Nocentini A., BANOĞLU E., Supuran C. T., ÇALIŞKAN B.

BIOORGANIC CHEMISTRY, cilt.95, 2020 (SCI-Expanded) identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 95
  • Basım Tarihi: 2020
  • Doi Numarası: 10.1016/j.bioorg.2019.103544
  • Dergi Adı: BIOORGANIC CHEMISTRY
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, BIOSIS, Biotechnology Research Abstracts, CAB Abstracts, Chimica, EMBASE, MEDLINE, Veterinary Science Database
  • Anahtar Kelimeler: Carbonic anhydrase, Benzimidazole, Sulfonamide, Carboxylic acid, Hydroxamic acid, IX, BIOACTIVITIES, DISCOVERY, DESIGN, TARGET
  • Gazi Üniversitesi Adresli: Evet

Özet

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 K-I 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 (K-I = 6.6 nM) and XII (K-I = 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 (K(I)s = 0.36-0.85 mu M for CA IX/XII).