Tags

Type your tag names separated by a space and hit enter

New racemic annulated pyrazolo[1,2-b]phthalazines as tacrine-like AChE inhibitors with potential use in Alzheimer's disease.
Eur J Med Chem. 2017 Oct 20; 139:280-289.EJ

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.

Authors+Show Affiliations

Department of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran, Iran.Department of Medicinal Chemistry, Faculty of Pharmacy, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.Department of Medicinal Chemistry, Faculty of Pharmacy, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.Department of Pharmaceutical Chemistry, College of Pharmacy, Aljouf University, Aljouf, Sakaka 2014, Saudi Arabia.Pharmaceutics Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran.Pharmaceutics Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran.Department of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran, Iran.Department of Cellular Biotechnology, Cell Science Research Center, Royan Institute for Biotechnology, ACECR, Isfahan, Iran.Drug Design and Development Research Center, Tehran University of Medical Sciences, Tehran, Iran.Pharmaceutics Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran; Department of Medicinal Chemistry, Faculty of Pharmacy and Neuroscience Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran.Department of Medicinal Chemistry and Pharmaceutical Sciences Research Center, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran.Department of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran, Iran; Department of Pharmaceutical Biomaterials and Medical Biomaterials Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran. Electronic address: Mehdi.khoobi@gmail.com.Department of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran, Iran; Department of Medicinal Chemistry, Faculty of Pharmacy and Neuroscience Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran. Electronic address: aforoumadi@yahoo.com.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

28803044

Citation

Jalili-Baleh, Leili, et al. "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, 2017, pp. 280-289.
Jalili-Baleh L, Nadri H, Moradi A, et al. New racemic annulated pyrazolo[1,2-b]phthalazines as tacrine-like AChE inhibitors with potential use in Alzheimer's disease. Eur J Med Chem. 2017;139:280-289.
Jalili-Baleh, L., Nadri, H., Moradi, A., Bukhari, S. N. A., 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, 139, 280-289. https://doi.org/10.1016/j.ejmech.2017.07.072
Jalili-Baleh L, et al. New Racemic Annulated Pyrazolo[1,2-b]phthalazines as Tacrine-like AChE Inhibitors With Potential Use in Alzheimer's Disease. Eur J Med Chem. 2017 Oct 20;139:280-289. PubMed PMID: 28803044.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - New racemic annulated pyrazolo[1,2-b]phthalazines as tacrine-like AChE inhibitors with potential use in Alzheimer's disease. AU - Jalili-Baleh,Leili, AU - Nadri,Hamid, AU - Moradi,Alireza, AU - Bukhari,Syed Nasir Abbas, AU - Shakibaie,Mojtaba, AU - Jafari,Mandana, AU - Golshani,Mostafa, AU - Homayouni Moghadam,Farshad, AU - Firoozpour,Loghman, AU - Asadipour,Ali, AU - Emami,Saeed, AU - Khoobi,Mehdi, AU - Foroumadi,Alireza, Y1 - 2017/07/31/ PY - 2016/12/19/received PY - 2017/04/23/revised PY - 2017/07/29/accepted PY - 2017/8/15/pubmed PY - 2017/10/19/medline PY - 2017/8/14/entrez KW - Acetylcholinesterase KW - Alzheimer's disease KW - Neuroprotective activity KW - Phthalazine KW - Tacrine KW - β-amyloid aggregation SP - 280 EP - 289 JF - European journal of medicinal chemistry JO - Eur J Med Chem VL - 139 N2 - 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. SN - 1768-3254 UR - https://www.unboundmedicine.com/medline/citation/28803044/New_racemic_annulated_pyrazolo[12_b]phthalazines_as_tacrine_like_AChE_inhibitors_with_potential_use_in_Alzheimer's_disease_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0223-5234(17)30594-9 DB - PRIME DP - Unbound Medicine ER -