Acetylcholinesterase and carbonic anhydrase inhibitory properties of novel urea and sulfamide derivatives incorporating dopaminergic 2-aminotetralin scaffolds |
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| Institution: | 1. Erzurum Technical University, Faculty of Science, Department of Basic Sciences, Erzurum, Turkey;2. Ataturk University, Faculty of Science, Department of Chemistry, Erzurum, Turkey;3. King Saud University, College of Science, Department of Zoology, Riyadh, Saudi Arabia;4. Department of Biophysics, School of Medicine, Bahcesehir University, Istanbul, Turkey;5. Faculty of Science and Arts, Department of Chemistry, Sutcu Imam University, Kahramanmaras, Turkey;6. Dipartimento di Chimica Ugo Schiff, Universita degli Studi di Firenze, Sesto Fiorentino (Firenze), Italy;7. Neurofarba Department, Section of Pharmaceutical and Nutraceutical Sciences, Universita degli Studi di Firenze, Sesto Fiorentino (Florence), Italy;1. Ataturk University, Faculty of Sciences, Department of Chemistry, Erzurum, Turkey;2. Erzurum Technical University, Faculty of Science, Department of Basic Sciences, Erzurum, Turkey;1. Bezmialem Vakif University, Faculty of Pharmacy, Department of Analytical and Medicinal Chemistry, 34093, Istanbul, Turkey;2. Department of Drug Sciences, University of Catania, Viale A. Doria 6 Ed. 2, Città Universitaria, I-95125, Catania, Italy;3. Sakarya University, Pamukova Vocational High School, 54900, Sakarya, Turkey;4. Molecular Modelling Laboratory, Department of Food Science, University of Parma, Parco Area delle Scienze 17/A, Parma 43124, Italy;5. Sakarya University, Faculty of Arts and Science, Department of Chemistry, 54055, Sakarya, Turkey;1. Department of Pharmaceutical Sciences, Birla Institute of Technology, Mesra, Ranchi 835215, India;2. Università degli Studi di Firenze, Polo Scientifico, Laboratorio di Chimica Bioinorganica, Rm. 188, Via della Lastruccia 3, 50019 Sesto Fiorentino (Firenze), Italy;3. Università degli Studi di Firenze, NEUROFARBA Department, Section of Pharmaceutical Chemistry, Via Ugo Schiff 6, 50019 Sesto Fiorentino (Florence), Italy;1. Cumhuriyet University, Vocational School of Health Services, 58140 Sivas, Turkey;2. Department of Chemistry, Faculty of Arts and Sciences, Gaziosmanpasa University, 60250 Tokat, Turkey;3. Department of Molecular Biology and Genetics, Faculty of Arts and Sciences, Gaziosmanpasa University, 60250 Tokat, Turkey;4. Department of Chemistry, Faculty of Science, Atatürk University, 25240 Erzurum, Turkey;5. Department of Zoology, College of Science, King Saud University, Riyadh, Saudi Arabia |
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| 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 2.61–3.69 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. |
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| Keywords: | Acetylcholine esterase Carbonic anhydrase Enzyme inhibition Sulfamide Urea Molecular docking Molecular dynamics (MD) simulations |
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