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    Synthesis, design, and cholinesterase inhibitory activity of novel 1,2,4-tri-azole Schiff bases: A combined experimental and computational approach
    (Elsevier, 2025) Medetalibeyoglu, Hilal; Atalay, Abdurrahman; Saglamtas, Ruya; Manap, Sevda; Ortaakarsu, Ahmet Bugra; Ekinci, Emel; Yuksek, Haydar
    Alzheimer's disease (AD), a progressive neurodegenerative disorder, is characterized by cholinergic dysfunction, necessitating the development of potent cholinesterase inhibitors for therapeutic intervention. In this research, a series of novel 1,2,4-triazole Schiff bases (S1-S8) was successfully synthesized and tested for their cholinesterase inhibitory activities both in vitro and in silico. 4-Hydroxy-3-methoxybenzaldehyde reacted with 4-methylbenzene sulfonyl chloride, then refluxed and recrystallized to form 4-formyl-2-methoxyphenyl 4-methyl benzenesulfonate, which combined with 4-amino-5-alkyl(aryl)-2,4-dihydro-3H-1,2,4-triazol-3-ones in acetic acid to yield Schiff bases. The synthesis yielded high-purity compounds with efficiency ranging from 87.5 % to 99.5 %, confirmed through IR, 1H NMR, 13C NMR, and UV-Vis spectroscopy. The biological evaluation showed that S4 demonstrated the strongest inhibition of acetylcholinesterase (AChE) with an IC50 of 3.00 mu M, significantly outperforming rivastigmine (IC50 = 8.95 mu M) and galantamine (IC50 = 29.5 mu M). Additionally, S7 emerged as the most effective inhibitor of butyrylcholinesterase (BChE), with an IC50 of 0.77 mu M, comparable to rivastigmine (IC50 = 0.62 mu M) and far stronger than galantamine (IC50 = 27.8 mu M). The Ki values reinforced the selective inhibition properties, with S4 (1.04 +/- 0.003 mu M) and S7 (0.61 +/- 0.001 mu M) showing high affinity for AChE and BChE, respectively. Molecular docking studies identified crucial it-it interactions and hydrogen bonding between the triazole derivatives and key enzyme residues, contributing to their high inhibitory potency. These interactions were further validated through molecular dynamics simulations, which confirmed the stability of the S4 and S7 complexes with AChE and BChE over extended periods. Computational analysis, including FMO studies, supported the experimental data, showing that HOMO-LUMO energy gaps significantly influenced the compounds' reactivity, stability, and inhibitory profiles. Overall, the study presents strong evidence that these novel 1,2,4-triazole Schiff bases possess potent and selective cholinesterase inhibition, notably S4 for AChE and S7 for BChE. These results suggest that these novel compounds have significant potential as selective cholinesterase inhibitors, particularly for Alzheimer's disease, warranting further in vivo studies.
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    Synthesis, molecular modeling investigation, molecular dynamic and ADME prediction of some novel Mannich bases derived from 1,2,4-triazole, and assessment of their anticancer activity
    (Taylor & Francis Inc, 2023) Manap, Sevda; Medetalibeyoglu, Hilal; Kilic, Ahsen; Karatas, Omer Faruk; Tuzun, Burak; Alkan, Muzaffer; Ortaakarsu, Ahmet Bugra
    A series of biologically active novel Mannich bases containing with a 1H-1,2,4-triazole-5-one ring were developed to evaluate the cytotoxic activity. For this purpose, the synthesized Schiff Bases (S1-5) were reacted with formaldehyde and morpholine, which is a secondary amine to yield novel N-Mannich bases (M1-5) via the Mannich reaction. The structures of the compounds (M1-5) were determined structurally employing 1H/13C-NMR, IR and elemental analysis. In this study, we evaluated the cytotoxic potential of the compounds (M1-5) on the human hypopharyngeal carcinoma FaDu cells. We found that the compound (M3) possesses a significant anticancer feature against FaDu cells that might be evaluated with further in vitro and in vivo studies to understand its anticancer potential better. Lastly, comparisons were made using molecular docking calculations to find the theoretical activities of the compounds (M1-5). The docking score parameter of the compound (M3) against the 2DO4 protein is -5.67, the docking score parameter against the 5JPZ protein is -5.72, and finally, the docking score parameter against the 2H80 protein is -5.50. Molecular dynamic calculations are made for 0-100 ns. The ADME/T calculations were performed to find the drug potential of the compounds (M1-5). The results suggest that our drug candidate compound exhibits strong potential for co-administration with the antigen structures, owing to the low rate of interactions that decreased over time.Communicated by Ramaswamy H. Sarma