Archives of Pharmacal Research

, Volume 38, Issue 4, pp 456–469 | Cite as

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

  • Ramin Miri
  • Omidreza Firuzi
  • Nima Razzaghi-AslEmail author
  • Katayoun Javidnia
  • Najmeh Edraki
Research Article


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 (6a6n). 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.


Alzheimer BACE-1 Inhibition Dihydropyridine 



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


  1. 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.CrossRefGoogle Scholar
  2. 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.CrossRefPubMedGoogle Scholar
  3. 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.CrossRefPubMedGoogle Scholar
  4. Citron, M. 2010. Alzheimer’s disease: strategies for disease modification. Nature Reviews Drug Discovery 9: 387–398.CrossRefPubMedGoogle Scholar
  5. 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.CrossRefGoogle Scholar
  6. 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.CrossRefPubMedCentralPubMedGoogle Scholar
  7. 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.CrossRefPubMedGoogle Scholar
  8. 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.CrossRefPubMedCentralPubMedGoogle Scholar
  9. 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.CrossRefGoogle Scholar
  10. Hantzsch, A. 1882. Ueber die synthese pyridinartiger verbindungen aus acetessigÃther und aldehydammoniak. Liebigs Annalen der Chemie 215(1): 1–82.CrossRefGoogle Scholar
  11. 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.CrossRefPubMedGoogle Scholar
  12. Jorgensen, W. 2014. The many roles of computation in drug discovery. Science 303: 1813–1818.CrossRefGoogle Scholar
  13. 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.CrossRefPubMedGoogle Scholar
  14. 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.CrossRefGoogle Scholar
  15. 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.CrossRefPubMedCentralPubMedGoogle Scholar
  16. Nussbaum, R.L., and C.E. Ellis. 2003. Alzheimer’s disease and Parkinson’s disease. New England Journal of Medicine 348: 1356–1364.CrossRefPubMedGoogle Scholar
  17. 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.CrossRefPubMedGoogle Scholar
  18. 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.CrossRefPubMedGoogle Scholar
  19. 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.CrossRefGoogle Scholar
  20. 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.CrossRefGoogle Scholar
  21. 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.CrossRefPubMedGoogle Scholar
  22. 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.CrossRefPubMedGoogle Scholar
  23. 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.CrossRefPubMedGoogle Scholar

Copyright information

© The Pharmaceutical Society of Korea 2014

Authors and Affiliations

  • Ramin Miri
    • 1
    • 2
  • Omidreza Firuzi
    • 1
  • Nima Razzaghi-Asl
    • 3
    Email author
  • Katayoun Javidnia
    • 1
  • Najmeh Edraki
    • 1
  1. 1.Medicinal and Natural Products Chemistry Research CenterShiraz University of Medical SciencesShirazIran
  2. 2.Department of Medicinal Chemistry, Faculty of PharmacyShiraz University of Medical SciencesShirazIran
  3. 3.Department of Medicinal Chemistry, School of PharmacyArdabil University of Medical SciencesArdabilIran

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