Dual-target ligand discovery for Alzheimer’s disease: triphenylphosphoranylidene derivatives as inhibitors of acetylcholinesterase and β-amyloid aggregation

Figures & data

Figure 1. Examples of approved AChE inhibitors used for AD.

Figure 2. Non-enzymatic activation of metriphonate.

Figure 3. Reported silicone-containing compounds and coumarin phosphazide derivative.

Scheme 1. Synthesis of compounds 5(a & b) in THF.

Scheme 2. Synthesis of compounds 8 (a–c) in THF.

Scheme 3. Synthesis of compounds 11 (a & b) in the presence of PdCl₂.

Scheme 4. Synthesis of compounds 13 (a & b) in boiling toluene in the presence of PdCl₂.

Scheme 5. Synthesis of compound 15 in refluxing toluene.

Figure 4. AChE IC₅₀ of the tested compounds compared to that of donepezil.

Table 1. IC₅₀ values of the tested compounds and the reference drug donepezil against AChE enzyme.

Compound	IC50 (nM)^a ± SD	Compound	IC50 (nM)^a ± SD
	206.25 ± 7.33		184.73 ± 9.22
	345.04 ± 12.3		508.03 ± 16.5
	157.78 ± 4.28		507.05 ± 22.1
	97.04 ± 2.93		248.82 ± 10.4
	426.35 ± 21.5		113.05 ± 4.82
Donepezil	34.42 ± 1.39

^aAverage of triplicate determination.

Table 2. BuChE IC₅₀, selectivity index, MMP-2 IC₅₀, and self-induced Aβ_1–42 aggregation IC₅₀.

Compound	BuChE IC50 (nM) ± SD	Selectivity index	MMP-2 IC50 (nM) ± SD	Self-induced Aβ1–42 aggregation IC50 (nM) ± SD
8c	84.83 ± 2.91	0.87	724.19 ± 16.5	302.36 ± 11.41
Donepezil	66.47 ± 2.51	1.93	–	115.94 ± 3.87
Imatinib	–	–	328.76 ± 12.1	–

Selectivity index = (BuChE IC₅₀)/(AChE IC₅₀).

Figure 5. (a) Kinetic study on the mechanism of AChE inhibition by compound 8c, Overlaid Lineweaver-Burk reciprocal plots of AChE initial velocity at increasing substrate concentration (15–60 nM) in the absence and in the presence of different concentrations of 8c. (b) Dixon plot of compound 8c showing the Ki value as negative intercept on the X-axis.

Figure 6. CC₅₀ and IC₅₀ of compound 8c.

Figure 7. Effects of compound 8c on the % of spontaneous alternations in the Y-maze test compared to the reference drug donepezil, the data shown are mean ± SD (n = 5). ^#p < 0.01 vs. control group.

Figure 8. Effects of compound 8c on the TLT in seconds in the step-down passive avoidance test by the scopolamine-induced cognitive impairment compared to the reference drug donepezil, the data shown are mean ± SD (n = 5). ^#p < 0.01 vs. control group.

Figure 9. Prediction of BBB permeability (pkCSM webserver).

Figure 10. Prediction of BBB permeability (SwissADME webserver).

Figure 11. 2D interaction of compound 8c (a) versus donepezil (b) with AChE active site.

Figure 12. 3D interaction of compound 8c with AChE active site.

Figure 13. 2D and 3D interactions of compound 8c with BuChE active site.