Synthesis, biological evaluation and computational studies of novel iminothiazolidinone benzenesulfonamides as potent carbonic anhydrase II and IX inhibitors

A series of iminothiazolidinone-sulfonamide hybrids (2a-k)was synthesized by heterocyclization of sul-fanilamide thioureas with methyl bromoacetate and characterized by spectroscopic techniques, mass andelemental analysis. The synthesized derivatives were screened against four relevant human (h) isoformsof carbonic anydrases (CAs, EC 4.2.1.1) I, II, IV and IX. These enzymes are involved in a variety of diseases,including glaucoma, retinitis pigmentosa, epilepsy, arthritis, and tumors. Derivatives2a-2kexhibited thebest inhibitory activity against the cytosolyc hCA II (KIs are reaching the sub-nanomolar range, 0.41–37.8nM) and against the tumor-associated isoform hCA IX (KIs are spanning between 24.3 and 368.3 nM). Thebinding mode of the reported iminothiazolidinone benzenesulfonamides within hCA II and IX catalyticclefts was investigated by docking studies.