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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

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 (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.

Keywords

Alzheimer BACE-1 Inhibition Dihydropyridine 

Notes

Acknowledgments

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

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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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