Identification of hCA I, hCA II, AChE and BChE Inhibitory Properties of Some Norcantharimide Derivatives; Molecular Docking, SAR and in silico ADME Studies

Abstract (3a R ,4 S ,7 R ,7a S )‐2‐Alkyl/aryl‐3a,4,7,7a‐tetrahydro‐1 H ‐4,7‐epoxyisoindole‐1,3(2 H )‐diones, which are norcantharimide derivatives, were synthesized and their effects on carbonic anhydrase I (hCA I) and II (hCA II), acetylcholinesterase (AChE), and butyrylcholinesterase (BChE) inhibitory activity were investigated. For enzyme activity studies, hCA I and II isoenzymes purified from human erythrocytes and the commercially available enzymes AChE and BChE, which are both markers and significantly affect the known symptoms of Alzheimer's disease, were used. The two derivatives exerted efficient inhibition with IC 50 =4.530 n M (K i =4.483) and 4.426 n M (K i =4.696) against hCA I and with IC 50 =3.825 n M (K i =3.854) and 3.457 n M (K i =3.292) against hCA II, respectively. The another two derivatives exerted considerable inhibition with IC 50 =0.526 n M (K i =0.224) and 0.575 n M (K i =0.292) against AChE and with IC 50 =0.135 n M (K i =0.057) and IC 50 =0.180 n M (K i =0.070) against BChE, respectively. The compounds showed activity at the nanomolar level. These remarkable inhibition results were compared with those of standard inhibitors (acetazolamide for hCA I and II and tacrine for AChE and BChE) of each enzyme, reported, and graphed. In addition, molecular docking studies were carried out by in silico methods and the structure–activity relationship was discussed. The poses of compound 4 c are presented along with the ligand–receptor interaction against all metabolic enzymes.