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 (K I s in the range of 0.7–62.3 nM), and IX, that is a validated anti-tumor target (K I s in the range of 3.0–50.9 nM), whereas interesting hydrophilicity-dependent inhibitory profiles were measured against isoform CA IV (K I s 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.