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Bioorg Med Chem. 2016 May 15;24(10):2318-29. doi: 10.1016/j.bmc.2016.04.002. Epub 2016 Apr 2.

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

Author information

1
Erzurum Technical University, Faculty of Science, Department of Basic Sciences, Erzurum, Turkey; Ataturk University, Faculty of Science, Department of Chemistry, Erzurum, Turkey.
2
Ataturk University, Faculty of Science, Department of Chemistry, Erzurum, Turkey. Electronic address: sgoksu@atauni.edu.tr.
3
Ataturk University, Faculty of Science, Department of Chemistry, Erzurum, Turkey.
4
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.
5
Department of Biophysics, School of Medicine, Bahcesehir University, Istanbul, Turkey.
6
Faculty of Science and Arts, Department of Chemistry, Sutcu Imam University, Kahramanmaras, Turkey.
7
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.

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.

KEYWORDS:

Acetylcholine esterase; Carbonic anhydrase; Enzyme inhibition; Molecular docking; Molecular dynamics (MD) simulations; Sulfamide; Urea

PMID:
27068142
DOI:
10.1016/j.bmc.2016.04.002
[Indexed for MEDLINE]

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