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...
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Veröffentlicht in: | Molecular diversity 2022-02, Vol.26 (1), p.409-428 |
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Hauptverfasser: | , , , , , , , , , , , |
Format: | Artikel |
Sprache: | eng |
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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 |
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ISSN: | 1381-1991 1573-501X |
DOI: | 10.1007/s11030-021-10248-w |