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5,6-Diphenyl triazine-thio methyl triazole hybrid as a new Alzheimer’s disease modifying agents

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Abstract

In this study, new derivatives of 5,6-diphenyl triazine-thio methyl triazole hybrid were designed, synthesized and evaluated as multifunctional agents for Alzheimer’s disease. Among all synthesized compounds, 4a and 4h showed the best inhibitory activities against BACE1 (40% and 37.5% μM inhibition at 50 µM, respectively). Molecular docking studies showed that compound 4a occupied the entire BACE1 enzyme and the thio triazine fragment deeply penetrates into S2 binding site via two hydrogen bonds with Thr72 and Gln73 amino acids. Different aromatic moieties occupy S′2 pocket via hydrophobic interactions. 6-Phenyl ring also had a potential hydrophobic interaction with S1 pocket. In vitro ChE inhibitory assay demonstrated that most of the derivatives exhibited more selectivity toward BuChE than AChE. 4c as the most potent BuChE inhibitor displayed an IC50 value of 6.4 µM, and 4b exhibited AChE inhibitory activity with 25.1% inhibition at 50 μM. Further, molecular docking studies revealed that the thiazolidinones moiety plays a key role in the inhibition mechanism by well fitting into the enzyme bounding pocket. Moreover, molecular docking study of 4a, 4b and 4c with ChE active site was also performed.

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Acknowledgements

The authors wish to thank the financial support of the Ahvaz branch, Islamic Azad University Ahvaz and the Vice-Chancellor for Research of Shiraz University of Medical Sciences (Grant No: 15280). We also thank National Institute for Medical Research Development, NIMAD (Grant No. 957334).

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Authors and Affiliations

  1. Department of Chemistry, Khozestan Science and Research Branch, Islamic Azad University, Ahvaz, Iran

    Mahnaz Yazdani

  2. Department of Chemistry, Ahvaz Branch, Islamic Azad University, Ahvaz, Iran

    Mahnaz Yazdani & Rashid Badri

  3. Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran

    Najmeh Edraki, Mehdi Khoshneviszadeh, Aida Iraji & Omidreza Firuzi

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  1. Mahnaz Yazdani
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Correspondence to Najmeh Edraki.

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Yazdani, M., Edraki, N., Badri, R. et al. 5,6-Diphenyl triazine-thio methyl triazole hybrid as a new Alzheimer’s disease modifying agents. Mol Divers 24, 641–654 (2020). https://doi.org/10.1007/s11030-019-09970-3

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  • DOI: https://doi.org/10.1007/s11030-019-09970-3

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