Acetylcholinesterase and carbonic anhydrase inhibitory properties of novel urea and sulfamide derivatives incorporating dopaminergic 2-aminotetralin scaffolds

• Published in: Bioorganic & medicinal chemistry 2016-05, Vol.24 (10), p.2318-2329
• Main Authors: Özgeriş, Bünyamin, Göksu, Süleyman, Polat Köse, Leyla, Gülçin, İlhami, Salmas, Ramin Ekhteiari, Durdagi, Serdar, Tümer, Ferhan, Supuran, Claudiu T.
• Format: Article
• Language: English
• Subjects: Acetylcholine esterase; Acetylcholinesterase - metabolism; Carbonic anhydrase; Carbonic Anhydrase I - metabolism; Carbonic Anhydrase II - metabolism; Carbonic Anhydrase Inhibitors - chemical synthesis; Carbonic Anhydrase Inhibitors - chemistry; Carbonic Anhydrase Inhibitors - pharmacology; Cholinesterase Inhibitors - chemical synthesis; Cholinesterase Inhibitors - chemistry; Cholinesterase Inhibitors - pharmacology; Enzyme inhibition; Humans; Molecular docking; Molecular Docking Simulation; Molecular dynamics (MD) simulations; Molecular Dynamics Simulation; Structure-Activity Relationship; Sulfamide; Sulfonamides - chemical synthesis; Sulfonamides - chemistry; Sulfonamides - pharmacology; Tetrahydronaphthalenes - chemical synthesis; Tetrahydronaphthalenes - chemistry; Tetrahydronaphthalenes - pharmacology; Urea; Urea - analogs & derivatives; Urea - chemical synthesis; Urea - pharmacology
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2016.04.002

A series of urea and sulfamides incorporating tetralin scaffolds were synthesized for their in vivo and in silico evaluation of hCA and AChE inhibition properties. All synthesized compounds showed important inhibition profiles against these enzymes. [Display omitted] •Three novel sulfamides derived from 2-aminotetralins were synthesized.•Three novel ureas derived from 2-aminotetralins were synthesized.•Synthesized sulfamide and ureas were converted to their phenolic derivatives.•The compounds showed effective hCA I, II and AChE inhibition.•The molecular mechanisms of inhibitions were investigated by in silico studies. 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 Ki values of 2.61–3.69nM against hCA I, 1.64–2.80nM against hCA II, and in the range of 0.45–1.74nM 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.