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New Isoindole‐1,3‐dione Substituted Sulfonamides as Potent Inhibitors of Carbonic Anhydrase and Acetylcholinesterase: Design, Synthesis, and Biological Evaluation
Author(s) -
Gündoğdu Saliha,
Türkeş Cüneyt,
Arslan Mustafa,
Demir Yeliz,
Beydemir Şükrü
Publication year - 2019
Publication title -
chemistryselect
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.437
H-Index - 34
ISSN - 2365-6549
DOI - 10.1002/slct.201903458
Subject(s) - carbonic anhydrase , chemistry , isoindole , protein data bank (rcsb pdb) , acetylcholinesterase , stereochemistry , tacrine , carbonic anhydrase i , docking (animal) , thiadiazoles , acetazolamide , isozyme , carbonic anhydrase ii , sulfamide , enzyme , isoindoline , medicinal chemistry , biochemistry , organic chemistry , medicine , nursing , anesthesia
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.