4-Cyanamido-Substituted Benzenesulfonamides Act as Dual Carbonic Anhydrase and Cathepsin Inhibitors

Bioorganic Chemistry 2023
Morteza Abdoli, Vesa Krasniqi, Alessandro Bonardi, Michael Gutschow, Claudiu T. Supuran, Raivis Žalubovskis

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.

Keywords
Carbonic anhydrases | Cathepsins | Cyanamides | Sulfonamides
DOI
10.1016/j.bioorg.2023.106725
Hyperlink
https://www.sciencedirect.com/science/article/pii/S0045206823003863?via%3Dihub

Abdoli, M., Krasniqi, V., Bonardi, A., Gutschow, M., Supuran, C., Žalubovskis, R. 4-Cyanamido-Substituted Benzenesulfonamides Act as Dual Carbonic Anhydrase and Cathepsin Inhibitors. Bioorganic Chemistry, 2023, Vol. 139, Article number 106725. ISSN 0045-2068. e-ISSN 1090-2120. Pieejams: doi:10.1016/j.bioorg.2023.106725

Publication language
English (en)