Synthesis, anticholinesterase activity, molecular docking, and molecular dynamic simulation studies of 1,3,4‐oxadiazole derivatives

Durmaz, Şeyma; Evren, Asaf Evrim; Sağlık, Begüm Nurpelin; Yurttaş, Leyla; Tay, Funda

doi:10.1002/ardp.202200294

Cited by 6 publications

(4 citation statements)

References 69 publications

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“…A particular molecule should possess five ideal qualities including MW of 500, a count of 5 H bond donors, and a count of 10 H bond acceptors. [22][23]…”

Section: Admet Prediction In-silicomentioning

confidence: 99%

In-silico Molecular Docking Studies of Methyl Oxadiazole Hybrids Inhibiting Acetylcholinesterase for Alzheimer’s Disease Treatment

2024

IJPQA

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Memory loss and cognitive decline are the main signs of Alzheimer’s disease (AD), a neurodegenerative brain illness that affects millions worldwide. AD is linked to aberrant beta-amyloid, low acetylcholine, oxidative stress, inflammation, and T protein aggregation. Low acetylcholine levels are one of the most important factors in Alzheimer’s disease since they are essential for cognitive processing and memory. This is why we’ve concentrated on ACHEIs and the cholinergic system. We used in-silico testing to find new and effective oxadiazole acetylcholinesterase inhibitors. This study created, docked, and predicted numerous novel oxadiazole scaffolds to find Alzheimer’s disease cholinesterase inhibitors. Offline tools like Protein Data Bank for PBD protein file downloads and Marvin Sketch for chemical structure representation enhance internet resources like PubChem, Swiss ADMET, and PyRx 0.9 for molecular docking research. We used Swiss Protein Data Bank Viewer for protein synthesis and https://plip-tool.biotec.plip.index.html for active site pocket prediction. Study results suggest 108 oxadiazole hybrids were used. Most compounds had zero or one Lipinski rule of five (RO5) violation. ADME research shows that all of these medicines have perfect pharmacokinetic features, including blood-brain barrier penetration. The docking tests demonstrate that our compounds have high target receptor binding energies of 8.1 to 12.3 kcal/mol. Similar to donepezil (12.76 K/cal), 2, 19, and 36 had 12 kcal/mol binding energies, 4, 11, and 32 had 11.5 kcal/mol, while compound 18 had 12.7 kcal/mol. Finally, our medications highly react with amino acid residues like Arg393, Arg525, Ala528 Asp400, and others. This binding approach is similar to donepezil, the gold standard. ADMET projections suggest these medications will have safer toxicological and pharmacokinetic profiles. The research aims to produce innovative AChE medications that restore brain acetyl choline levels, relieve Alzheimer’s disease symptoms and promote cognitive development.

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“…A particular molecule should possess five ideal qualities including MW of 500, a count of 5 H bond donors, and a count of 10 H bond acceptors. [22][23]…”

Section: Admet Prediction In-silicomentioning

confidence: 99%

In-silico Molecular Docking Studies of Methyl Oxadiazole Hybrids Inhibiting Acetylcholinesterase for Alzheimer’s Disease Treatment

2024

IJPQA

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“…Indeed, these findings and previous reports are in harmony. [25][26][27][28] However, we also wanted to investigate complex stability versus time and environmental changes such as water and electrolytes, hence, molecular simulation study was run for the most active compound 7a.…”

Section: Ache Inhibitory Activitymentioning

confidence: 99%

“…The experiment was conducted as stated in our previous study. [25] 4.2.2 | β-Secratase inhibition activity…”

Section: Ache and Bche Inhibitionmentioning

confidence: 99%

Design and synthesis of phenoxy methyl‐oxadiazole compounds against Alzheimer's disease

Evren,

Nuha,

Özkan

et al. 2024

Archiv der Pharmazie

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This study examines the synthesis and evaluation of 11 newly developed compounds as potential anti‐Alzheimer's agents that occur via cholinesterase and β‐secretase inhibition. The compounds were tested for their inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) using the modified Ellman method. The results showed that several compounds exhibited significant inhibition of AChE, particularly compounds 6d, 7a, and 7e, which demonstrated high inhibitory activity at lower concentrations, with IC50 values of 0.120, 0.039, and 0.063 µM, respectively. However, the compounds showed limited effectiveness against BChE, with only a few compounds exhibiting moderate inhibition. Compound 7e showed an inhibitory effect against BACE‐1 close to that of the standard drug. Structural analysis revealed that the compounds with substituted benzothiazole and thiazole moieties exhibited the most promising inhibitory activity. This study provides valuable insights into the potential of these synthesized derivatives as a treatment against Alzheimer's disease. Moreover, the structure, stability, and properties of the active compounds were further investigated using density functional theory calculations. As a final note, the utilization of molecular docking and molecular dynamics simulation studies allowed us to elucidate the action mechanism of the active compounds and gain insights into the structure–activity relationship against AChE and β‐secretase proteins. These computational techniques provide valuable information on the binding modes, interactions with target enzymes, dynamic behavior, and conformational changes of the compounds, enabling a comprehensive understanding of their biological activity.

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“…The molecular dynamic simulation was performed following the completion of the system setup. The radius of gyration (Rg), root mean square fluctuation (RMSF), and root mean square deviation (RMSD) values were calculated by the Desmond application Schrödinger Release 2020, Desmond, Schrödinger, LLC, New York, NY, USA (2020) and perused to previous literatures (39)(40).…”

Section: In Silico Studiesmentioning

confidence: 99%

In silico studies and in vitro microsomal metabolism of potent MetAP2 inhibitor and in vivo tumor suppressor for prostate cancer: A thioether-triazole hybrid

Coşkun

Birgül

Evren

et al. 2023

Acibadem Univ Saglik Bilim Derg

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Background/aim: The in-vitro microsomal metabolism of (S)-3-((2,4,6-trimethylphenyl)thio)-4-(4-fluorophenyl)-5-(1-(6-methoxynaphtalene-2-yl)ethyl)-4H-1,2,4-triazole (SGK636), an anticancer drug candidate was studied using pig microsomal preparations fortified with NADPH to identify the potential S-oxidation and S-dealkylation metabolites. Materials and methods: In the present study, the sulfoxide metabolite was synthesized, purified and characterized by chromatographic and spectroscopic methods. SGK636, the S-oxidation and S-dealkylation metabolites were then separated by a reversed phase LC-MS, with UV detection and with an HP-TLC system. The results from the in-vitro microsomal metabolic experiments showed that SGK636 produced the corresponding S-oxidation metabolite (sulfoxide) which was observed by LC-MS, LC-MS/MS and HP-TLC with the identical Rt and Rfx100 values and UV/MS spectra in comparison with the authentic compounds, but no any S-dealkylation metabolite was detected. Results: The present results were proved with molecular docking and molecular dynamic studies. Since sulfoxidation process can be reversible and it may partly explain the low amount of sulfoxide metabolite in our experiment, we also incubated the sulphoxide. No conversion back to the substrate (SGK636) was observed, but it produced the corresponding sulphone metabolite. In order to establish if SGK636 is autooxidized, the substrate was also incubated in buffer under standard incubation conditions, but no any autooxidation was observed into the corresponding sulfoxide. We also did a stability work for SGK636-SO (sulfoxide) in buffer to see any possible autooxidation to sulphone or reduction back to SGK636. No conversion was observed in either way. The substrate seems to be stable to metabolic reactions and to autooxidation which could be an advantage in terms of its pharmacological activity. Conclusion: The present metabolic and study indicates that SGK 636 underwent S-oxidation. In order to identify the responsible oxydative enzyme, molecular docking and molecular dynamic studies were performed. CYP3A4 was found to be responsible enzyme for S-oxidation.

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Synthesis, anticholinesterase activity, molecular docking, and molecular dynamic simulation studies of 1,3,4‐oxadiazole derivatives

Cited by 6 publications

References 69 publications

In-silico Molecular Docking Studies of Methyl Oxadiazole Hybrids Inhibiting Acetylcholinesterase for Alzheimer’s Disease Treatment

In-silico Molecular Docking Studies of Methyl Oxadiazole Hybrids Inhibiting Acetylcholinesterase for Alzheimer’s Disease Treatment

Design and synthesis of phenoxy methyl‐oxadiazole compounds against Alzheimer's disease

In silico studies and in vitro microsomal metabolism of potent MetAP2 inhibitor and in vivo tumor suppressor for prostate cancer: A thioether-triazole hybrid

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