Sulfonamide-Incorporated Bis(α-Aminophosphonates) as Promising Carbonic Anhydrase Inhibitors: Design, Synthesis, Biological Evaluation, and X-Ray Crystallographic Studies
Archiv der Pharmazie 2024
Marjan Sobati, Morteza Abdoli, Andrea Angeli, Alessandro Bonardi, Marta Ferraroni, Claudiu T. Supuran, Raivis Žalubovskis

A novel series of sulfonamide-incorporated bis(α-aminophosphonates) acting as effective carbonic anhydrase (CA, EC 4.2.1.1) inhibitors is reported. The synthesized bivalent ligands were tested against five human (h) isoforms, hCA I, hCA II, hCA VII, hCA IX, and hCA XIII. Such derivatives showed high activity and selectivity against the cancer-related, membrane-bound isoform hCA IX, and among them, compound 5h, tetraisopropyl (1,3-phenylenebis{[(4-sulfamoylphenyl)amino]methylene})bis(phosphonate) showed a KI of 15.1 nM, being highly selective against this isoform over all other investigated ones (hCA I/IX = 42; hCA II/IX = 6, hCA VII/IX = 3, hCA XIII/IX = 5). Therefore, compound 5h could be a potential lead for the development of selective anticancer agents. The newly developed sulfonamides were also found effective inhibitors against the cytosolic hCA XIII isoform. Compound 5i displayed the best inhibition against this isoform with a KI of 17.2 nM, equal to that of the well-known inhibitor acetazolamide (AAZ), but significantly more selective over all other tested isoforms (hCA I/XIII = 239; hCA II/XIII = 23, hCA VII/XIII = 2, hCA IX/XIII = 3) compared to AAZ.


Keywords
bis-sulfonamides | carbonic anhydrases | crystallography | multivalency | α-aminophosphonates
DOI
10.1002/ardp.202400038
Hyperlink
https://onlinelibrary.wiley.com/doi/10.1002/ardp.202400038

Sobati, M., Abdoli, M., Angeli, A., Bonardi, A., Ferraroni, M., Supuran, C., Žalubovskis, R. Sulfonamide-Incorporated Bis(α-Aminophosphonates) as Promising Carbonic Anhydrase Inhibitors: Design, Synthesis, Biological Evaluation, and X-Ray Crystallographic Studies. Archiv der Pharmazie, 2024, Vol. 357, No. 7, Article number 2400038. ISSN 0365-6233. e-ISSN 1521-4184. Pieejams: doi:10.1002/ardp.202400038

Publication language
English (en)
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