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. 2023 Dec;38(1):2281264.
doi: 10.1080/14756366.2023.2281264. Epub 2023 Nov 20.

Synthesis, biological evaluation, and computational studies of N-benzyl pyridinium-curcumin derivatives as potent AChE inhibitors with antioxidant activity

Nafisah M Al-Rifai  1 , Nemeh M Al-Khalileh  2 , Jalal A Zahra  2 , Musa I El-Barghouthi  3 , Fouad H Darras  4
Affiliations

Synthesis, biological evaluation, and computational studies of N-benzyl pyridinium-curcumin derivatives as potent AChE inhibitors with antioxidant activity

Nafisah M Al-Rifai et al. J Enzyme Inhib Med Chem. 2023 Dec.

Abstract

A library of N-benzylpyridinium-based compounds, 7a-j and 8a-j, was designed and synthesised as potential acetylcholinesterase) AChE (inhibitors. An in vitro assay for the synthesised compounds showed that most compounds had significant AChE inhibitory activities at the nanomolar and submicromolar levels. The benzyl (8a) and fluoro (8b) derivatives were the most active, with IC50 values ≤56 nM. Compound 7f, which had a benzyl moiety, showed the highest potency among all the target compounds, with an IC50 value of 7.5 ± 0.19 nM against AChE, which was higher than that of the activities of tacrine (IC50 = 30 ± 0.2 nM) and donepezil (IC50 = 14 ± 0.12 nM). Compounds with vanillin moieties exhibited antioxidant activity. Among the tested compounds, four derivatives (7f, 7 g, 8f, and 8 g) exhibited superior AChE inhibitory activity, with Ki values of 6-16 nM, which were potent in the same range as the approved drug, donepezil. These compounds showed moderate antioxidant activities, as indicated by the results of the ABTS assay.

Keywords: Acetylcholinesterase inhibitors; Alzheimer’s disease; antioxidants; docking study; pyridinium; synthesis.

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Conflict of interest statement

No potential conflict of interest was reported by the author(s).

Figures

None
Graphical abstract
Figure 1.
Figure 1.
Donepezil (1) and reported donepezil analogues that function as AChE inhibitors.
Figure 2.
Figure 2.
Design strategy of the target compounds.
Scheme 1.
Scheme 1.
The general route to prepare the α,β-unsaturated carbonyl compounds.
Scheme 2.
Scheme 2.
Synthesis of the target benzyl pyridinium salts.
Figure 3.
Figure 3.
Lineweaver-Burk plot of the substrate-velocity curve of AChE activity with different substrate (ATC) concentrations (32–2 mM) in the absence and presence of compound 7a.
Figure 4.
Figure 4.
Slopes of Lineweaver–Burk plots versus inhibitor 7a concentration.
Figure 5.
Figure 5.
Superposition of the X-ray (blue) and docked (light green) structures of donepezil within the active site of AChE.
Figure 6.
Figure 6.
Superposition of the top-scored structure of target compound 7f (pink) and the X-ray structure of donepezil (blue) within the active site of AChE.
Figure 7.
Figure 7.
Interaction mode of the target compound 7f in the active site of ACh.
Figure 8.
Figure 8.
(a) Superposition of the top-scored structures for compounds 7e (green) and 7f (pink) within the active site of AChE. (b) Interaction mode of compound 7e in the active site of AChE.
See this image and copyright information in PMC

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