Synthesis and evaluation of novel arylisoxazoles linked to tacrine moiety: in vitro and in vivo biological activities against Alzheimer’s disease

Alzheimer’s disease (AD) is now ranked as the third leading cause of death after heart disease and cancer. There is no definite cure for AD due to the multi-factorial nature of the disease, hence, multi-target-directed ligands (MTDLs) have attracted lots of attention. In this work, focusing on the e...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Veröffentlicht in:Molecular diversity 2022-02, Vol.26 (1), p.409-428
Hauptverfasser: Rastegari, Arezoo, Safavi, Maliheh, Vafadarnejad, Fahimeh, Najafi, Zahra, Hariri, Roshanak, Bukhari, Syed Nasir Abbas, Iraji, Aida, Edraki, Najmeh, Firuzi, Omidreza, Saeedi, Mina, Mahdavi, Mohammad, Akbarzadeh, Tahmineh
Format: Artikel
Sprache:eng
Schlagworte:
Online-Zugang:Volltext
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
Beschreibung
Zusammenfassung:Alzheimer’s disease (AD) is now ranked as the third leading cause of death after heart disease and cancer. There is no definite cure for AD due to the multi-factorial nature of the disease, hence, multi-target-directed ligands (MTDLs) have attracted lots of attention. In this work, focusing on the efficient cholinesterase inhibitory activity of tacrine, design and synthesis of novel arylisoxazole-tacrine analogues was developed. In vitro acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibition assay confirmed high potency of the title compounds. Among them, compounds 7l and 7b demonstrated high activity toward AChE and BChE with IC 50 values of 0.050 and 0.039 μM, respectively. Both compounds showed very good self-induced Aβ aggregation and AChE-induced inhibitory activity (79.4 and 71.4% for compound 7l and 61.8 and 58.6% for compound 7b , respectively). Also, 7l showed good anti-BACE1 activity with IC 50 value of 1.65 µM. The metal chelation test indicated the ability of compounds 7l and 7b to chelate biometals (Zn 2+ , Cu 2+ , and Fe 2+ ). However, they showed no significant neuroprotectivity against Aβ-induced damage in PC12 cells. Evaluation of in vitro hepatotoxicity revealed comparable toxicity of compounds 7l and 7b with tacrine. In vivo studies by Morris water maze (MWM) task demonstrated that compound 7l significantly reversed scopolamine-induced memory deficit in rats. Finally, molecular docking studies of compounds 7l and 7b confirmed establishment of desired interactions with the AChE, BChE, and BACE1 active sites. Graphic Abstract
ISSN:1381-1991
1573-501X
DOI:10.1007/s11030-021-10248-w