4-Substituted benzenesulfonamides featuring cyclic imides moieties exhibit potent and isoform-selective carbonic anhydrase II/IX inhibition

Abstract

The synthesis, characterization and biological evaluation of series of cyclic imides incorporating the 4-sulfamoylbenzamide scaffold (16–29) is disclosed. The compounds were designed by application of the “tail approach” to the aromatic sulfonamide scaffold and prepared by reacting the proper acid anhydride with 4-(hydrazinecarbonyl)benzenesulfonamide (15). Phtalimides and cyclic imides are biologically privileged scaffolds, endowed with versatile biological activity, such as an anti-proliferative action. The compounds were investigated for the inhibition of four human (h) isoforms of zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1), and more specifically against the cytosolic hCA I and II and the transmembrane hCA IV and IX. Most screened sulfonamides exhibited great potency in inhibiting CA isoforms II, widely involved in glaucoma and other pathologies (KIs in the range of 0.7–62.3 nM), and IX, that is a validated anti-tumor target (KIs in the range of 3.0–50.9 nM), whereas interesting hydrophilicity-dependent inhibitory profiles were measured against isoform CA IV (KIs in the range of 3.9–428.6 nM). In silico studies were carried out to assess the binding mode of selected derivatives to hCA II, IV and IX.