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    Synthesis, characterization, and computational study of novel carvacrol-based 2-aminothiol and sulfonic acid derivatives as metabolic enzyme inhibitors
    (Elsevier, 2024) Bytyqi-Damoni, Arlinda; Uc, Eda Mehtap; Bora, Rifat Emin; Bilgicli, Hayriye Genc; Alagoz, Mehmet Abdullah; Zengin, Mustafa; Gulcin, Lhami
    Eight new 2-aminothiols (69-96%) and three new sulfonic acids (51-76%) were synthesized and characterized by NMR and HRMS spectra. This study presents the inhibitory effects of a series of novel carvacrol-based 2-aminothiol and sulfonic acid derivatives (3a-f,4a-c) against human carbonic anhydrase I and II isozymes (hCA I and II) acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and alpha-glycosidase. Ki values were calculated as 12.52 +/- 3.61-335.65 +/- 60.56 nM for hCA I, 12.20 +/- 3.59-389.69 +/- 119.41 nM for hCA II, 1.79 +/- 0.56-84.86 +/- 23.34 nM for AChE, 6.57 +/- 2.54-88.05 +/- 21.05 nM for BChE and 14.63 +/- 4.76-116.39 +/- 33.70 nM alpha-glucosidase enzymes. Also, the inhibition effects of novel carvacrol-based 2-aminothiol (3a -h) and sulfonic acid derivatives (4a -c) were compared to standard and clinically used inhibitors of acetazolamide, Tacrine and acarbose, respectively. Molecular modeling studies of novel compounds, docking scores, and free binding energies were calculated. The activity results of the compounds were found to be compatible with the docking scores. Molecular dynamics studies were conducted with the best activity against CA I and CA II compounds, 4b (IC50: 4.76 nM) and 4a (IC50: 4.36 nM), respectively. In Dynamic Simulation studies, it was observed that the compounds remained stable at the active sites of the proteins.
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    Synthesis, characterization, evaluation of metabolic enzyme inhibitors and in silico studies of thymol based 2-amino thiol and sulfonic acid compounds
    (Elsevier Ireland Ltd, 2022) Bora, Rifat Emin; Bilgicli, Hayriye Genc; Uc, Eda Mehtap; Alagoz, Mehmet Abdullah; Zengin, Mustafa; Gulcin, Ilhami
    Eight new aminothiols (4a-g and 5) and three new sulfonic acid derivatives (6a-c) were synthesized, and their structures were characterized. Inhibitory effects of the obtained compounds on carbonic anhydrase I and II isoforms (hCA I and hCA II), butyrylcholinesterase (BChE) and acetylcholinesterase (AChE), enzymes were investigated. The newly synthesized compounds have inhibited hCA I with Kis ranging from 7.11 +/- 1.46 nM (6a) to 670.52 +/- 300.41 nM (4b) and, hCA II with Kis ranging from 16.83 +/- 5.72 nM (6a) to 453.34 +/- 208.56 nM (4c). Acetazolamide was employed as the positive control for both hCA isoforms (K-i for hCA I 198.81 +/- 14.13 nM and K-i for hCA II 211.42 +/- 13.10 nM), and among the new compounds obtained, it was observed that there were compounds that were active at much lower nM levels. All compounds were also evaluated for inhibition of AChE and BChE. They inhibited AChE and BChE enzymes in the range of Ki 5.24 +/- 2.27 (6c) -48.44 +/- 21.82 (4g) for AChE and 4.86 +/- 0.64 (6c) -51.75 +/- 12.56 (4a) for BChE, and the results were compared with the standard inhibitor Tacrine (K-i: 14.20 +/- 8.83 nM toward AChE and K-i: 3.39 +/- 1.91 nM for BChE). Cholinesterase (BChE and AChE) inhibitory abilities of all synthesized molecules were also performed in situ and molecular docking and molecular dynamics (MD) simulation studies. The molecular coupling scores of the compounds and the free binding energies calculated by MM/GBSA were found to be compatible. Examining the results obtained from this study shows that it may have the potential to develop new drugs to treat some global patients such as glaucoma and Alzheimer's disease (AD).