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    Determination of the inhibition profiles of pyrazolyl-thiazole derivatives against aldose reductase and ?-glycosidase and molecular docking studies
    (Wiley-V C H Verlag Gmbh, 2020) Demir, Yeliz; Taslimi, Parham; Kocyigit, Umit M.; Akkus, Musa; Ozaslan, Muhammet Serhat; Duran, Hatice Esra; Budak, Yakup
    Aldose reductase (AR) is the first and rate-limiting enzyme of the polyol pathway, which converts glucose to sorbitol in an NADPH-dependent reaction. alpha-Glycosidase breaks down starch and disaccharides to glucose. Hence, inhibition of these enzymes can be regarded a considerable approach in the treatment of diabetic complications. AR was purified from sheep liver using simple chromatographic methods. The inhibitory effects of pyrazolyl-thiazoles ((3aR,4S,7R,7aS)-2-(4-{1-[4-(4-bromophenyl)thiazol-2-yl]-5-(aryl)-4,5-dihydro-1H-pyrazol-3-yl}phenyl)-3a,4,7,7a-tetrahydro-1H-4,7-methanoisoindole-1,3(2H)-dione derivatives;3a-i) on AR and alpha-glycosidase enzymes were investigated. All compounds showed a good inhibitory action against AR and alpha-glycosidase. Among these compounds, compound3dexhibited the best inhibition profiles against AR, with aK(i)value of 7.09 +/- 0.19 mu M, whereas compound3eshowed the lowest inhibition effects, with aK(i)value of 21.89 +/- 1.87 mu M. Also, all compounds showed efficient inhibition profiles against alpha-glycosidase, withK(i)values in the range of 0.43 +/- 0.06 to 2.30 +/- 0.48 mu M, whereas theK(i)value of acarbose was 12.60 +/- 0.78 mu M. Lastly, molecular modeling approaches were implemented to predict the binding affinities of compounds against AR and alpha-glycosidase. In addition, the ADME analysis of the molecules was performed.
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    Phenolic Compounds: Investigating Their Anti-Carbonic Anhydrase, Anti-Cholinesterase, Anticancer, Anticholinergic, and Antiepileptic Properties Through Molecular Docking, MM-GBSA, and Dynamics Analyses
    (Korean Institute Chemical Engineers, 2025) Akkus, Musa; Kirici, Mahinur; Poustforoosh, Alireza; Erdogan, Mehmet Kadir; Gundogdu, Ramazan; Tuzun, Burak; Taslimi, Parham
    Phenolic compounds are a new class of Carbonic Anhydrase inhibitors (CAIs). Despite numerous advancements in treatment approaches, cancer continues to be a growing health problem worldwide. In our study, we tested the effects of 4-hydroxy-3-methoxyacetophenone (1), doxycycline hydrochloride (2), 5,7-dichloro-8-hydroxyquinoline (3), methyl 3,4,5-trihydroxybenzoate (4), 2-hydroxy-4-methylacetophenone (5), 6-hydroxy-4-methylcoumarin (6), and 2,5-dihydroxyacetophenone (7) on Achetylcholynesterase (AChE), Butrycholynesterase (BChE), and Human Carbonic anhydrase I (hCA I) enzymes. The U2OS human osteosarcoma cell line was used to determine the anticancer potential of these phenolic compounds. The effects of the compounds on proliferation and colony formation were analyzed using the Neutral Red Uptake (NRU) assay and the clonogenic assay. The Ki values of arachidonoyl dopamine, 2,4,6-trihydroxybenzaldehyde, and 3,4-dihydroxy-5-methoxybenzoic acid were 203.80, 1170.00, and 910.00 mM, respectively, for hCA I, and 75.25, 354.00, and 1510.00 mM, respectively, for Human Carbonic anhydrase II (hCA II). Additionally, IC50 values from in vivo studies were found to range from 173.25 to 1360.00 mM for CA I and CA II, respectively, using CO2-hydratase activity methods. The NRU assay results revealed that the compounds had a dose-dependent cytotoxic effect on U2OS cells. The IC50 values of the compounds in U2OS osteosarcoma cells were determined to be > 100, 93.7, 81.4, 26.9, > 100, 53.1, and > 100 mu M, respectively. Notably, methyl 3,4,5-trihydroxybenzoate (4), the compound with the lowest IC50 value, significantly suppressed colony formation at 5 and 10 mu M concentrations. These results demonstrated that the phenolic compounds used in in vivo studies could inhibit approximately 30% of the CO2-hydratase activity of the total CA enzyme of rat erythrocytes. Furthermore, the anticancer potential of the tested compounds suggests that these molecules could pave the way for the development of new approaches in cancer treatment. The activities of the seven molecules studied were compared against AChE (PDB ID: 4M0E), BChE (PDB ID: 5NN0), hCA I (PDB ID: 2CAB), and E3 ubiquitin-protein ligase (PDB ID: 4HG7) proteins. The binding free energy of the molecule with the highest docking score is computed using MM/GBSA techniques. Finally, molecular dynamics simulations were performed between 6-hydroxy-4-methylcoumarin and the 4M0E protein over a 0-200 ns interval.