title: 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 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.
authors.affiliation: Erzurum Technical University, Faculty of Science, Department of Basic Sciences, Erzurum, Turkey; Ataturk University, Faculty of Science, Department of Chemistry, Erzurum, Turkey.
authors.forename: Bünyamin
authors.initials: B
authors.lastname: Özgeriş
authors.affiliation: Ataturk University, Faculty of Science, Department of Chemistry, Erzurum, Turkey. Electronic address: sgoksu@atauni.edu.tr.
authors.forename: Süleyman
authors.initials: S
authors.lastname: Göksu
authors.affiliation: Ataturk University, Faculty of Science, Department of Chemistry, Erzurum, Turkey.
authors.forename: Leyla
authors.initials: L
authors.lastname: Polat Köse
authors.affiliation: Ataturk University, Faculty of Science, Department of Chemistry, Erzurum, Turkey; King Saud University, College of Science, Department of Zoology, Riyadh, Saudi Arabia. Electronic address: igulcin@atauni.edu.tr.
authors.forename: İlhami
authors.initials: İ
authors.lastname: Gülçin
authors.affiliation: Department of Biophysics, School of Medicine, Bahcesehir University, Istanbul, Turkey.
authors.forename: Ramin Ekhteiari
authors.initials: RE
authors.lastname: Salmas
authors.affiliation: Department of Biophysics, School of Medicine, Bahcesehir University, Istanbul, Turkey.
authors.forename: Serdar
authors.initials: S
authors.lastname: Durdagi
authors.affiliation: Faculty of Science and Arts, Department of Chemistry, Sutcu Imam University, Kahramanmaras, Turkey.
authors.forename: Ferhan
authors.initials: F
authors.lastname: Tümer
authors.affiliation: Dipartimento di Chimica Ugo Schiff, Universita degli Studi di Firenze, Sesto Fiorentino (Firenze), Italy; Neurofarba Department, Section of Pharmaceutical and Nutraceutical Sciences, Universita degli Studi di Firenze, Sesto Fiorentino (Florence), Italy.
authors.forename: Claudiu T
authors.initials: CT
authors.lastname: Supuran
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism*; D024401:Carbonic Anhydrase I / Q000378:metabolism; D024402:Carbonic Anhydrase II / Q000378:metabolism; D002257:Carbonic Anhydrase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013764:Tetrahydronaphthalenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D014508:Urea / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*
chemical_list: D002257:Carbonic Anhydrase Inhibitors; D002800:Cholinesterase Inhibitors; D013449:Sulfonamides; D013764:Tetrahydronaphthalenes; C006561:2-aminotetralin; D014508:Urea; D000110:Acetylcholinesterase; D024401:Carbonic Anhydrase I; D024402:Carbonic Anhydrase II
keywords: Acetylcholine esterase; Carbonic anhydrase; Enzyme inhibition; Molecular docking; Molecular dynamics (MD) simulations; Sulfamide; Urea