4-Cyanamido-substituted benzenesulfonamides act as dual carbonic anhydrase and cathepsin inhibitors

• Published in: Bioorganic chemistry 2023-10, Vol.139, p.106725-106725, Article 106725
• Main Authors: Abdoli, Morteza, Krasniqi, Vesa, Bonardi, Alessandro, Gütschow, Michael, Supuran, Claudiu T., Žalubovskis, Raivis
• Format: Article
• Language: English
• Subjects: Benzenesulfonamides; Carbonic Anhydrase Inhibitors - chemistry; Carbonic Anhydrase Inhibitors - pharmacology; Carbonic anhydrases; Carbonic Anhydrases - metabolism; Cathepsins; Cyanamides; Structure-Activity Relationship; Sulfonamides
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2023.106725

[Display omitted] •Synthesis of novel N-cyano-N-acyl-4-aminobenzenesulfonamides via acylation of potassium (4-sulfamoylphenyl)cyanamide.•Biochemical characterization as inhibitors of carbonic anhydrases and two cathepsins was performed.•Dual-active compounds against enzymes involved in neuropathic pain are reported. A set of novel N-cyano-N-substituted 4-aminobenzenesulfonamide derivatives were synthesized and investigated for their inhibitory activity against four cytosolic carbonic anhydrase (CA, EC 4.2.1.1) isoforms (hCA I, II, VII and XIII) and two cathepsins (S and B). N-alkyl/benzyl-substituted derivatives were revealed to be very potent inhibitors against brain-associated hCA VII, but inactive against both cathepsins. On the other hand, N-acyl-substituted derivatives displayed significant inhibitory activities against cathepsin S, but only moderate to poor inhibitory potency against hCA VII. Both hCA VII and cathepsin S have recently been validated as therapeutic targets in neuropathic pain. This study provided an excellent starting point for further structural optimization of this class of bifunctional compounds to enhance their inhibitory activity and selectivity against hCA VII and cathepsin S and to achieve new compounds with an attractive dual mechanism of action as anti-neuropathic agents.