Synthesis, design, and cholinesterase inhibitory activity of novel 1,2,4-tri-azole Schiff bases: A combined experimental and computational approach

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dc.authoridOrtaakarsu, Ahmet Bugra/0000-0003-3317-9505
dc.contributor.authorMedetalibeyoglu, Hilal
dc.contributor.authorAtalay, Abdurrahman
dc.contributor.authorSaglamtas, Ruya
dc.contributor.authorManap, Sevda
dc.contributor.authorOrtaakarsu, Ahmet Bugra
dc.contributor.authorEkinci, Emel
dc.contributor.authorYuksek, Haydar
dc.date.accessioned2025-05-04T16:47:12Z
dc.date.available2025-05-04T16:47:12Z
dc.date.issued2025
dc.departmentSivas Cumhuriyet Üniversitesi
dc.description.abstractAlzheimer'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.
dc.description.sponsorshipScientific Research Project Fund of Sivas Cumhuriyet University (CUBAP) [RGD-020]
dc.description.sponsorshipSome of the computations reported in this research were carried out at the TUBITAK ULAKBIM, High Performance and Grid Computing Center (TRUBA resources) . This work was supported by the Scientific Research Project Fund of Sivas Cumhuriyet University (CUBAP) under the project number RGD-020.
dc.identifier.doi10.1016/j.ijbiomac.2025.141350
dc.identifier.issn0141-8130
dc.identifier.issn1879-0003
dc.identifier.pmid39986523
dc.identifier.scopus2-s2.0-85218343657
dc.identifier.scopusqualityQ1
dc.identifier.urihttps://doi.org/10.1016/j.ijbiomac.2025.141350
dc.identifier.urihttps://hdl.handle.net/20.500.12418/35525
dc.identifier.volume306
dc.identifier.wosWOS:001433509000001
dc.identifier.wosqualityQ1
dc.indekslendigikaynakWeb of Science
dc.indekslendigikaynakScopus
dc.indekslendigikaynakPubMed
dc.language.isoen
dc.publisherElsevier
dc.relation.ispartofInternational Journal of Biological Macromolecules
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanı
dc.rightsinfo:eu-repo/semantics/closedAccess
dc.snmzKA_WOS_20250504
dc.subjectCholinesterase inhibitors
dc.subjectSchiff base
dc.subjectTriazole
dc.subjectDFT
dc.subjectMolecular docking
dc.titleSynthesis, design, and cholinesterase inhibitory activity of novel 1,2,4-tri-azole Schiff bases: A combined experimental and computational approach
dc.typeArticle

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