New Isoindole‐1,3‐dione Substituted Sulfonamides as Potent Inhibitors of Carbonic Anhydrase and Acetylcholinesterase: Design, Synthesis, and Biological Evaluation

Herein, a series of isoindole‐1,3‐dione substituted sulfonamide derivatives ( 3 , 4 a – k ) were designed, synthesized, and biologically evaluated, as inhibitors of carbonic anhydrase (CA) and acetylcholinesterase (AChE). CA and AChE inhibitory activities of newly synthesized isoindole‐1,3‐dione substituted sulfonamides compounds ( 3 , 4 a–k ) towards the hCA I, II, and AChE were evaluated utilizing the Verpoorte's and Ellman's assays and checked against that of standard inhibitors, acetazolamide (AAZ) and tacrine (TAC). The developed compounds ( 3 , 4 a – k ) showed the potent hCA isoenzyme inhibitory effect with K i constants ranging from 7.96 to 48.34 nM, compared to AAZ ( K i s; 436.20 nM for hCA I and 93.53 nM for hCA II). Among these derivatives; 1,3‐dioxo‐1,3‐dihydroisobenzofuran‐5‐carbocyclic acid ( 3 ) and benzyl‐1,3‐dioxo‐2‐(4‐sulfomophenyl)isoindoline‐5‐carboxylate ( 4 i ) determined to be effective AChE inhibitors ( K i s, 103.51 and 108.92 nM, respectively); these compounds were almost as potent to TAC ( K i , 109.75 nM). Furthermore, molecular docking studies of derivatives 3 and 4 i were carried out utilizing the crystal structures of hCA I (PDB Code: 4WR7), II (PDB Code: 4HT0) isozymes and AChE (PDB Code: 4EY7) receptors to study their binding interactions.