Amido/ureidosubstituted benzenesulfonamides-isatin conjugates as low nanomolar/subnanomolar inhibitors of the tumor-associated carbonic anhydrase isoform XII

• Published in: European journal of medicinal chemistry 2016-03, Vol.110, p.259-266
• Main Authors: Eldehna, Wagdy M., Fares, Mohamed, Ceruso, Mariangela, Ghabbour, Hazem A., Abou-Seri, Sahar M., Abdel-Aziz, Hatem A., Abou El Ella, Dalal A., Supuran, Claudiu T.
• Format: Article
• Language: English
• Subjects: Amido/ureido sulfonamides; Benzenesulfonamides; Carbonic anhydrase; Carbonic Anhydrase Inhibitors - chemical synthesis; Carbonic Anhydrase Inhibitors - chemistry; Carbonic Anhydrase Inhibitors - pharmacology; Carbonic Anhydrases - metabolism; Humans; Isatin; Isatin - chemical synthesis; Isatin - chemistry; Isatin - pharmacology; Protein Isoforms - antagonists & inhibitors; Protein Isoforms - metabolism; Structure-Activity Relationship; Sulfonamides - chemical synthesis; Sulfonamides - chemistry; Sulfonamides - pharmacology; Tumor-associated isoforms; Urea - analogs & derivatives; Urea - chemical synthesis; Urea - pharmacology
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2016.01.030

By using a molecular hybridization approach, two series of amido/ureidosubstituted benzenesulfonamides incorporating substituted-isatin moieties were synthesized. The prepared derivatives were in vitro evaluated for their inhibitory activity against human carbonic anhydrase (hCA, EC 4.2.1.1) I, II (cytosolic) and IX, XII (transmembrane, tumor-associated) isoforms. All these isoforms were inhibited in variable degrees by the sulfonamides reported here. hCA I was inhibited with KIs in the range of 7.9–894 nM, hCA II in the range of 7.5–1645 nM (with one compound having a KI > 10 μM); hCA IX in the range of 5.0–240 nM, whereas hCA XII in the range of 0.47–2.83 nM. As all these isoforms are involved in various pathologies, in which their inhibition can be exploited therapeutically, the derivatives reported here may represent interesting extensions to the field of CA inhibitors of the sulfonamide type. Two series of amido and ureido-sulfonamides conjugated with isatins were synthesized and evaluated for their inhibitory activity against a panel of hCAs; I, II (cytosolic) and IX, XII (transmembrane). [Display omitted] •Different sulfonamides incorporating amido or ureido linkers were synthesized.•Inhibitory activity of these sulfonamides was evaluated toward hCA I, II, IX and XII.•9, 6b-g, 10c and 10e displayed outstanding potency against CA XII (KI: 0.47–0.71 nM).•Other derivatives emerged as single-digit nanomolar CA XII inhibitors (1.17–2.83 nM).