Chiral Sulfamoyl‐Carbamate Derivatives Bearing a Naphthalene Motif as Potent Cholinesterase Inhibitors: Synthesis, Characterization, DFT Study, Molecular Docking, and Molecular Dynamics Simulations

Abstract

ABSTRACT N ‐(substituted sulfamoyl)‐carbamates containing a naphthalene moiety have been synthesized in good yields using a simple process, which relies on a nucleophilic substitution between chlorosulfonyl isocyanate, aromatic amines, and enantiopure ( R )‐aryl ethyl carbinols based on the naphthalene core. These later were obtained through kinetic resolution via CAL‐B catalyzed alkaline hydrolysis. The synthesized compounds' structures were confirmed by nuclear magnetic resonance, Fourier transform infrared and mass spectroscopy. Using Lipinski's rule of five and pharmacological features offering further information about their therapeutic potential and drug‐likeness. Density functional theory (DFT) calculations at the B3LYP6‐311G (d,p) basis set were performed for assessing their active sites. Furthermore, molecular docking and molecular dynamics simulations identified stable binding interactions of the synthesized compounds in the active sites of human acetylcholinesterase enzyme (PDB: 4BDT) and butyrylcholinesterase enzyme (PDB: 4BDS). Strong binding affinities for the human acetylcholinesterase enzyme (−6900 to −9773 kcal/mol) and butyrylcholinesterase enzyme (−7475 to −8665 kcal/mol) were found by docking investigations when compared to reference drugs Rivastigmine, Donepezil, and Tacrine. Compounds (R)‐ 1,2‐dihydroacenaphthylen‐1‐yl(3,4‐dihydroisoquinolin‐2(1H)‐yl)sulfonylcarbamate (1c) and ( R) ‐ 1‐(7‐methoxynaphthalen‐2‐yl)ethyl(3,4‐dihydro‐isoquinolin‐2(1H)yl)sulfonylcarbamate (2c) demonstrated the most favorable activity, evidencing distinct electronic profiles in DFT analyses and stable interactions in MD simulations. These compounds represent promising candidates for further development as potential cholinesterase inhibitors.