Inhibition studies of new ureido-substituted sulfonamides incorporating a GABA moiety against human carbonic anhydrase isoforms I–XIV

• Published in: Bioorganic & medicinal chemistry 2014-12, Vol.22 (24), p.6768-6775
• Main Authors: Ceruso, Mariangela, Antel, Sabrina, Vullo, Daniela, Scozzafava, Andrea, Supuran, Claudiu T.
• Format: Article
• Language: English
• Subjects: Carbonic anhydrase; Carbonic Anhydrase Inhibitors - chemical synthesis; Carbonic Anhydrase Inhibitors - chemistry; Carbonic Anhydrase Inhibitors - metabolism; Carbonic Anhydrases - chemistry; Carbonic Anhydrases - genetics; Carbonic Anhydrases - metabolism; GABA; gamma-Aminobutyric Acid - chemistry; Humans; Isoenzymes - antagonists & inhibitors; Isoenzymes - genetics; Isoenzymes - metabolism; Isoform-selective CA inhibitors; Protein Binding; Recombinant Proteins - biosynthesis; Recombinant Proteins - chemistry; Recombinant Proteins - genetics; Structure-Activity Relationship; Sulfanilamides - chemical synthesis; Sulfanilamides - chemistry; Sulfanilamides - metabolism; Ureido-substituted sulfonamide
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2014.10.041

[Display omitted] Reaction of γ-Boc-GABA, prepared by protecting the γ-amino moiety of the amino butyric acid with the tert-butyloxycarbonyl (Boc) protecting group, with 4-methyl/ethyl benzenesulfonamide, followed by removal of the Boc protecting group in 3M HCl afforded the corresponding hydrochlorides, which were further derivatized by reaction with a varying of aryl isocyanates to give a new classes of ureido substituted benzenesulfonamide containing a GABA moiety. Inhibition studies of the human carbonic anhydrase (CA, EC 4.2.1.1) isoforms, CA I–XIV with these new compounds revealed that they possess moderate–weak inhibition potency against hCA III, IV, VA, VI and XIII, rather efficient inhibitory power against hCA I, VI, and IX, and excellent inhibition of the physiologically relevant hCA II and VII, as well as of the two tumor-associated isoforms CA IX and XII. The inhibition profile of the new ureido-substituted benzenesulfonamides reported here is thus very different from the corresponding ureido-substituted analogs incorporating sulfanilamide, which were previously investigated as inhibitors of some of these enzymes.