Acetylcholinesterase and Carbonic Anhydrase Inhibitory Properties of Novel Urea and Sulfamide Derivatives Incorporating Dopaminergic 2-Aminotetralin Scaffolds

Abstract

In the present study a series of urea and sulfamide compounds incorporating the tetralin scaffolds were synthesized and evaluated for their acetylcholinesterase (AChE), human carbonic anhydrase (CA, EC 4.2.1.1) isoenzyme I, and II (hCA I and hCA II) inhibitory properties. The urea and their sulfamide analogs were synthesized from the reactions of 2-aminotetralins with N,N-dimethylcarbamoyl chloride and N,N-dimethylsulfamoyl chloride, followed by conversion to the corresponding phenols via O-demethylation with BBr3. The novel urea and sulfamide derivatives were tested for inhibition of hCA I, II and AChE enzymes. These derivatives exhibited excellent inhibitory effects, in the low nanomolar range, with K-i values of 2.61-3.69 nM against hCA I, 1.64-2.80 nM against hCA II, and in the range of 0.45-1.74 nM against AChE. In silico techniques such as, atomistic molecular dynamics (MD) and molecular docking simulations, were used to understand the scenario of the inhibition mechanism upon approaching of the ligands into the active site of the target enzymes. In light of the experimental and computational results, crucial amino acids playing a role in the stabilization of the enzyme-inhibitor adducts were identified. (C) 2016 Elsevier Ltd. All rights reserved.