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Inhibitors of Alzheimer’s BACE-1 with 3,5-bis-N-(aryl/heteroaryl) carbamoyl-4-aryl-1,4-dihydropyridine structure

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Abstract

β-site amyloid precursor protein cleaving enzyme (BACE-1) is a validated target for Alzheimer therapy due to its distinctive role in pathogenesis of AD. In the present contribution, a series of new 3,5-bis-N-(aryl/heteroaryl) carbamoyl-4-aryl-1,4-dihydropyridine structures were synthesized as BACE-1 inhibitors (6a–6n). In vitro BACE-1 inhibitory activities were determined by enzymatic fluorescence resonance energy transfer assay. Synthesized dihydropyridine (DHP) analogues exhibited weak to good inhibitory activities while 6i, 6n and 6a were found to be the most potent molecules with 83.76, 79.45 and 72.47 % BACE-1 inhibition at 10 μM, respectively. Structure binding/activity relationship elucidations revealed that superior BACE-1 inhibitory activities were observed for DHP derivatives bearing fused/non-fused thiazole groups and particularly 3,5-bis-N-(6-ethoxy-2-benzothiazolyl) moiety. Binding maps showed that enhanced activity may be attributed to the additional H-bond and hydrophobic interactions with S2–S3 subpockets of BACE-1.

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References

  • Al-Nadaf, A., G. Abu Sheikha, and M.O. Taha. 2010. Elaborate ligand-based pharmacophore exploration and QSAR analysis guide the synthesis of novel pyridinium-based potent beta-secretase inhibitory leads. Bioorganic and Medicinal Chemistry 1(18): 3088–3115.

    Article  Google Scholar 

  • Biran, Y., C.L. Masters, K.J. Barnham, A.I. Bush, and P.A. Adlard. 2009. Pharmacotherapeutic targets in Alzheimer’s disease. Journal of Cellular and Molecular Medicine 13(1): 61–86.

    Article  CAS  PubMed  Google Scholar 

  • Choi, S.J., J.H. Cho, I. Im, S.D. Lee, J.Y. Jang, Y.M. Oh, Y.K. Jung, E.S. Jeon, and Y.C. Kim. 2010. Design and synthesis of 1,4-dihydropyridine derivatives as BACE-1 inhibitors. European Journal of Medicinal Chemistry 45(6): 2578–2590.

    Article  CAS  PubMed  Google Scholar 

  • Citron, M. 2010. Alzheimer’s disease: strategies for disease modification. Nature Reviews Drug Discovery 9: 387–398.

    Article  CAS  PubMed  Google Scholar 

  • Clemens, R.J., and J.A. Hyatt. 1985. Acetoacetylation with 2,2,6-trimethyl-4H-1,3-dioxin-4-one: a convenient alternative to diketene. Journal of Organic Chemistry 50: 2431–2433.

    Article  CAS  Google Scholar 

  • Creed, M.C., and N.W. Milgram. 2010. Amyloid-modifying therapies for Alzheimer’s disease: therapeutic progress and its implications. Age 32(3): 365–384.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Edraki, N., O. Firuzi, A. Foroumadi, R. Miri, A. Madadkar-Sobhani, M. Khoshneviszadeh, and A. Shafiee. 2013. Phenylimino-2H-chromen-3-carboxamide derivatives as novel small molecule inhibitors of β-Secretase (BACE1). Bioorganic and Medicinal Chemistry 21(8): 2396–2412.

    Article  CAS  PubMed  Google Scholar 

  • Gaulton, A., L.J. Bellis, A.P. Bento, J. Chambers, M. Davies, A. Hersey, Y. Light, S. McGlinchey, D. Michalovich, and B. Al-Lazikani. 2012. ChEMBL: a large-scale bioactivity database for drug discovery. Nucleic Acids Research 40(D1): D1100–D1107.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Ghosh, A.K., M. Brindisi, and J. Tang. 2012. Developing β-secretase inhibitors for treatment of Alzheimer’s disease. Journal of Neurochemistry 1: 71–83.

    Article  Google Scholar 

  • Hantzsch, A. 1882. Ueber die synthese pyridinartiger verbindungen aus acetessigÃther und aldehydammoniak. Liebigs Annalen der Chemie 215(1): 1–82.

    Article  Google Scholar 

  • Huang, W.H., R. Sheng, and Y.Z. Hu. 2009. Progress in the development of nonpeptidomimetic BACE 1 inhibitors for Alzheimers disease. Current Medicinal Chemistry 16(14): 1806–1820.

    Article  CAS  PubMed  Google Scholar 

  • Jorgensen, W. 2014. The many roles of computation in drug discovery. Science 303: 1813–1818.

    Article  Google Scholar 

  • Laurie, R., T. Alasdair, and R.M. Jackson. 2006. Methods for the prediction of protein-ligand binding sites for structure-based drug design and virtual ligand screening. Current Protein and Peptide Science 7(5): 395–406.

    Article  CAS  PubMed  Google Scholar 

  • Luo, Y., B. Bolon, S. Kahn, B.D. Bennett, S. Babu-Khan, P. Denis, W. Fan, H. Kha, J. Zhang, and Y. Gong. 2001. Mice deficient in BACE1, the Alzheimer’s beta-secretase, have normal phenotype and abolished beta-amyloid generation. Nature Neuroscience 4(3): 2001–2003.

    Article  Google Scholar 

  • Morris, G.M., R. Huey, W. Lindstrom, M.F. Sanner, R.K. Belew, D.S. Goodsell, and A.J. Olson. 2009. AutoDock4 and AutoDockTools4: automated docking with selective receptor flexibility. Journal of Computational Chemistry 30(16): 2785–2791.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Nussbaum, R.L., and C.E. Ellis. 2003. Alzheimer’s disease and Parkinson’s disease. New England Journal of Medicine 348: 1356–1364.

    Article  CAS  PubMed  Google Scholar 

  • Putta, S., and P. Beroza. 2007. Shapes of things: computer modeling of molecular shape in drug discovery. Current Topics in Medicinal Chemistry 7(15): 1514–1524.

    Article  CAS  PubMed  Google Scholar 

  • Razzaghi-Asl, N., O. Firuzi, B. Hemmateenejad, K. Javidnia, N. Edraki, and R. Miri. 2013. Design and synthesis of Novel 3,5-bis-N-(aryl/heteroaryl) carbamoyl-4-aryl-1,4-dihydropyridines as small molecule BACE-1 inhibitors. Bioorganic and Medicinal Chemistry 21(22): 6893–6909.

    Article  CAS  PubMed  Google Scholar 

  • Sellers, R.P., L.D. Alexander, V.A. Johnson, C.C. Lin, J. Savage, R. Corral, J.T. Moss, S. Slugocki, E.K. Singh, and M.R. Davis. 2010. Design and synthesis of Hsp90 inhibitors: exploring the SAR of Sansalvamide A derivatives. Bioorganic and Medicinal Chemistry Letter 18: 6822–6856.

    Article  CAS  Google Scholar 

  • Van Der Spoel, D., E. Lindahl, B. Hess, G. Groenhof, A.E. Mark, and H.J.C. Berendsen. 2005. GROMACS: fast, flexible, and free. Journal of Computational Chemistry 26: 1701–1718.

    Article  Google Scholar 

  • Wallace, A.C., R.A. Laskowski, and J.M. Thornton. 1995. LIGPLOT: a program to generate schematic diagrams of protein-ligand interactions. Protein Engineering 8: 127–134.

    Article  CAS  PubMed  Google Scholar 

  • Yan, R., M.J. Bienkowski, M.E. Shuck, H. Miao, M.C. Tory, A.M. Pauley, J.R. Brashler, N.C. Stratman, W.R. Mathews, A.E. Buhl, D.B. Carter, A.G. Tomasselli, L.A. Parodi, R.L. Heinrikson, and M.E. Gurney. 1999. Membrane-anchored aspartyl protease with Alzheimer’s disease [beta]-secretase activity. Nature 402: 533–537.

    Article  CAS  PubMed  Google Scholar 

  • Zuo, Z., X. Luo, W. Zhu, J. Shen, X. Shen, H. Jiang, and K. Chen. 2005. Molecular docking and 3D-QSAR studies on the binding mechanism of statine-based peptidomimetics with β-secretase. Bioorganic and Medicinal Chemistry 13: 2121–2131.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was financially supported by research council of Shiraz University of Medical Sciences.

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Authors and Affiliations

  1. Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, PO Box 3288-71345, Shiraz, Iran

    Ramin Miri, Omidreza Firuzi, Katayoun Javidnia & Najmeh Edraki

  2. Department of Medicinal Chemistry, Faculty of Pharmacy, Shiraz University of Medical Sciences, PO Box 1583-71345, Shiraz, Iran

    Ramin Miri

  3. Department of Medicinal Chemistry, School of Pharmacy, Ardabil University of Medical Sciences, PO Box 56189-53141, Ardabil, Iran

    Nima Razzaghi-Asl

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  1. Ramin Miri
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  2. Omidreza Firuzi
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Correspondence to Nima Razzaghi-Asl.

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Miri, R., Firuzi, O., Razzaghi-Asl, N. et al. Inhibitors of Alzheimer’s BACE-1 with 3,5-bis-N-(aryl/heteroaryl) carbamoyl-4-aryl-1,4-dihydropyridine structure. Arch. Pharm. Res. 38, 456–469 (2015). https://doi.org/10.1007/s12272-014-0401-x

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  • DOI: https://doi.org/10.1007/s12272-014-0401-x

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