Dual targeting of acetylcholinesterase and tau aggregation: Design, synthesis and evaluation of multifunctional deoxyvasicinone analogues for Alzheimer’s disease

• Published in: Bioorganic chemistry 2021-11, Vol.116, p.105354-105354, Article 105354
• Main Authors: Manzoor, Shoaib, Gabr, Moustafa T., Rasool, Bisma, Pal, Kavita, Hoda, Nasimul
• Format: Article
• Language: English
• Subjects: Acetylcholinesterase; Acetylcholinesterase - metabolism; Alzheimer Disease - drug therapy; Alzheimer Disease - metabolism; Alzheimer’s disease; Cholinesterase Inhibitors - chemical synthesis; Cholinesterase Inhibitors - chemistry; Cholinesterase Inhibitors - pharmacology; Deoxyvasicinone derivatives; Dose-Response Relationship, Drug; Drug Design; Humans; Molecular Structure; Neuroprotective Agents - chemical synthesis; Neuroprotective Agents - chemistry; Neuroprotective Agents - pharmacology; Protein Aggregates - drug effects; Quinazolines - chemical synthesis; Quinazolines - chemistry; Quinazolines - pharmacology; Structure-Activity Relationship; Tau aggregation; tau Proteins - antagonists & inhibitors; tau Proteins - metabolism
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2021.105354

[Display omitted] •New multitargeted ligands 11(a-j) and 15(a-g) were designed and synthesized.•11f significantly inhibited AChE activity and cellular tau oligomerization at single-dose screening (10 µM).•11f possessed significant neuroprotection against tau-expressing SH-SY5Y cells incubated with Aβ oligomers.•BBB permeation assay predicted that 11f was able to cross the BBB. Development of multitargeted ligands have demonstrated remarkable efficiency as potential therapeutics for Alzheimer’s disease (AD). Herein, we reported a new series of deoxyvasicinone analogues as dual inhibitor of acetylcholinesterase (AChE) and tau aggregation that function as multitargeted ligands for AD. All the multitargeted ligands 11(a-j) and 15(a-g) were designed, synthesized, and validated by 1HNMR, 13CNMR and mass spectrometry. All the synthesized compounds 11(a-j) and 15(a-g) were screened for their ability to inhibit AChE, BACE1, amyloid fibrillation, α-syn aggregation, and tau aggregation. All the screened compounds possessed weak inhibition of BACE-1, Aβ42 and α-syn aggregation. However, several compounds were identified as potential hits in the AChE inhibitory screening assay and cellular tau aggregation screening. Among all compounds, 11f remarkably inhibited AChE activity and cellular tau oligomerization at single-dose screening (10 µM). Moreover, 11f displayed a half-maximal inhibitory concentration (IC50) value of 0.91 ± 0.05 µM and half-maximal effective concentration (EC50) value of 3.83 ± 0.51 µM for the inhibition of AChE and cellular tau oligomerization, respectively. In addition, the neuroprotective effect of 11f was determined in tau-expressing SH-SY5Y cells incubated with Aβ oligomers. These findings highlighted the potential of 11f to function as a multifunctional ligand for the development of promising anti-AD drugs.