New racemic annulated pyrazolo[1,2-b]phthalazines as tacrine-like AChE inhibitors with potential use in Alzheimer's disease

Leili Jalili-Baleh, Hamid Nadri, Alireza Moradi, Bukhari Syed Nasir Abbas, Mojtaba Shakibaie, Mandana Jafari, Mostafa Golshani, Farshad Homayouni Moghadam, Loghman Firoozpour, Ali Asadipour, Saeed Emami, Mehdi Khoobi, Alireza Foroumadi

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

A novel series of tacrine-like compounds 7a-u possessing a fused pyrazolo[1,2-b]phthalazine structure were designed and synthesized as potent and selective inhibitors of AChE. The in-vitro biological assessments demonstrated that several compounds had high anti-AChE activity at nano-molar level. The more promising compound 7l with IC50 of 49 nM was 7-fold more potent than tacrine and unlike tacrine, it was highly selective against AChE over BuChE. The cell-based assays against hepatocytes (HepG2) and neuronal cell line (PC12) revealed that 7l had significantly lower hepatotoxicity compared to tacrine, with additional neuroprotective activity against H2O2-induced damage in PC12 cells. This compound could also inhibit AChE-induced and self-induced Aβ peptide aggregation. The advantages including synthetic accessibility, high potency and selectivity, low toxicity, adjunctive neuroprotective and Aβ aggregation inhibitory activity, make this compound as a new multifunctional lead for Alzheimer's disease drug discovery.

Original languageEnglish
Pages (from-to)280-289
Number of pages10
JournalEuropean Journal of Medicinal Chemistry
Volume139
DOIs
Publication statusPublished - 1 Jan 2017
Externally publishedYes

Fingerprint

Phthalazines
Tacrine
Alzheimer Disease
Agglomeration
PC12 Cells
Hep G2 Cells
Drug Discovery
Inhibitory Concentration 50
Toxicity
Hepatocytes
Assays
Cells
Cell Line
Peptides

Keywords

  • Acetylcholinesterase
  • Alzheimer's disease
  • Neuroprotective activity
  • Phthalazine
  • Tacrine
  • β-amyloid aggregation

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

Cite this

New racemic annulated pyrazolo[1,2-b]phthalazines as tacrine-like AChE inhibitors with potential use in Alzheimer's disease. / Jalili-Baleh, Leili; Nadri, Hamid; Moradi, Alireza; Syed Nasir Abbas, Bukhari; Shakibaie, Mojtaba; Jafari, Mandana; Golshani, Mostafa; Homayouni Moghadam, Farshad; Firoozpour, Loghman; Asadipour, Ali; Emami, Saeed; Khoobi, Mehdi; Foroumadi, Alireza.

In: European Journal of Medicinal Chemistry, Vol. 139, 01.01.2017, p. 280-289.

Research output: Contribution to journalArticle

Jalili-Baleh, L, Nadri, H, Moradi, A, Syed Nasir Abbas, B, Shakibaie, M, Jafari, M, Golshani, M, Homayouni Moghadam, F, Firoozpour, L, Asadipour, A, Emami, S, Khoobi, M & Foroumadi, A 2017, 'New racemic annulated pyrazolo[1,2-b]phthalazines as tacrine-like AChE inhibitors with potential use in Alzheimer's disease', European Journal of Medicinal Chemistry, vol. 139, pp. 280-289. https://doi.org/10.1016/j.ejmech.2017.07.072
Jalili-Baleh, Leili ; Nadri, Hamid ; Moradi, Alireza ; Syed Nasir Abbas, Bukhari ; Shakibaie, Mojtaba ; Jafari, Mandana ; Golshani, Mostafa ; Homayouni Moghadam, Farshad ; Firoozpour, Loghman ; Asadipour, Ali ; Emami, Saeed ; Khoobi, Mehdi ; Foroumadi, Alireza. / New racemic annulated pyrazolo[1,2-b]phthalazines as tacrine-like AChE inhibitors with potential use in Alzheimer's disease. In: European Journal of Medicinal Chemistry. 2017 ; Vol. 139. pp. 280-289.
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