Design and synthesis of sulfonamides incorporating a biotin moiety: Carbonic anhydrase inhibitory effects, antiproliferative activity and molecular modeling studies

[Display omitted] •Conjugation of biotin and sulfonamide motifs with amide- and urea-based tethers afforded strong CA inhibitors.•Low nanomolar activities were achieved.•Tertiary amides afforded good selectivity towards CA IX and XII isoforms.•Compound 2k displayed interesting antiproliferative activities against glioblastoma, triple-negative breast cancer, and pancreatic carcinoma cell lines.•Molecular Docking calculations were used to predict the binding properties of the most relevant inhibitors with CAs and sodium-dependent multivitamin transporter protein (SMVT) Sulfonamides constitute an important class of classical carbonic anhydrase (CA, EC 4.2.1.1) inhibitors. Herein we have accomplished the conjugation of biotin with an ample number of sulfonamide motifs with the aim of testing them in vitro as inhibitors of the human carbonic anhydrase (hCA) isoforms I and II (cytosolic isozymes), as well as hCA IX and XII (transmembrane, tumor-associated enzymes). Most of these newly synthesized compounds exhibited interesting inhibition profiles, with activities in the nanomolar range. The presence of a 4-F-C6H4 moiety, also found in SLC-0111, afforded an excellent selectivity towards the tumor-associated hypoxia-induced hCA isoform XII with an inhibition constant (KI) of 4.5 nM. The 2-naphthyl derivative was the most potent inhibitor against hCA IX (KI = 6.2 nM), 4-fold stronger than AAZ (KI = 25 nM) with very good selectivity. Some compounds were chosen for antiproliferative activity testing against a panel of 3 human tumor cell lines, one compound showing anti-proliferative activity on glioblastoma, triple-negative breast cancer, and pancreatic carcinoma cell lines.