Discovery of novel isoflavone derivatives as AChE/BuChE dual-targeted inhibitors: synthesis, biological evaluation and molecular modelling

Figures & data

Figure 1. Structures of currently marketed cholinesterase inhibitors.

Figure 2. Chemical Structure of the hit compound G.

Table 1. Chemical structures of synthesised isoflavone derivatives.

Compound	n	R1	R2	R
1	2	OH	CH3
2	3	H	CH3
3	4	H	CH3
4	2	H	CH3
5	3	H	CH3
6	4	H	CH3
7	2	H	CH3
8	3	H	CH3
9	4	H	CH3
10	2	H	CH3
11	3	H	CH3
12	4	H	CH3
13	2	H	CH3
14	2	H	H
15	2	H	H
16	2	H
17	1	H	CH3
18	2	H	CH3
19	2	H	CH3
20	2	H	CH3

Scheme 1. The general procedure for the synthesis of compounds 1–20. (i): K₂CO₃, acetone, Br(CH₂)_nBr, 60 °C; (ii): RH (amines), K₂CO₃, DMF/Acetonitrile, 100 °C, 3 h; (iii): 40% HBr, 120 °C, 3 h; (iv): piperidine, THF r.t. 10 h; (v): formononetin, K₂CO₃, acetone; (vi) K₂CO₃, 3-bromopropionic acid, acetone, 60 °C, 2 days; (vii) DMF, N, N-diisopropylethylamine, piperidine, 12 h, r.t.

Table 2. In vitro inhibition of AChE and BuChE for compounds 1–20.

	Inhibition % at 50 μM		IC50 (μM)
Name	AChE	BuChE	AChE	BuChE
G	n.d.^a	n.d.	1.47	3.37
1	71.10	95.74	10.3	4.12
2	28.34	97.00	n.d.	23.2
3	85.65	98.11	46.39	11.1
4	58.66	84.13	100.4	141.3
5	25.38	91.32	n.d.	103.6
6	63.76	94.77	106.6	68.08
7	3.68	45.74	n.d.	n.d.
8	2.42	60.63	n.d.	15.6
9	0.72	37.92	n.d.	n.d.
10	3.34	2.72	n.d.	n.d.
11	−6.27	−18.48	n.d.	n.d.
12	5.47	−16.87	n.d.	n.d.
13	17.61	−6.62	n.d.	n.d.
14	79.38	99.86	9.75	7.66
15	75.22	99.88	57.74	7.19
16	100.34	99.74	4.60	5.92
17	0.54	−2.83	n.d.	n.d.
18	−2.36	5.59	n.d.	n.d.
19	−11.56	53.03	n.d.	9.59
20	−4.84	−5.49	n.d.	n.d.
Donepezil	64.82	n.d.	1.05	n.d.
Iso-OMPA	n.d.	94.28	n.d.	5.78

^a n.d.: not determined.

Figure 3. (a) 2D schematic diagram of potential interactions between compound 16 and AChE. (b) The predicted binding mode of compound 16 with AChE.

Figure 4. (a) 2D schematic diagram of potential interactions between compound 16 and BuChE. (b) The predicted binding mode of compound 16 with BuChE.

Table 3. Predicted pharmacokinetic properties of compounds 1, 3, 14, 15 and 16.

Compound	AlogP98	PSA-2D	Solubility level	Absorption level	BBB level	PPB	CYP2D6
1	3.647	68.259	2	0	2	True	True
3	4.532	47.443	2	0	1	True	True
14	3.664	59.328	2	0	1	True	True
15	3.208	59.328	2	0	2	True	True
16	4.945	50.796	2	0	1	True	False
G	4.267	47.443	2	0	1	True	True

AlogP98: Lipophilicity descriptor; PSA-2D: Polar surface area; AlogP98: Lipophilicity descriptor; PSA-2D: Polar surface area; Solubility Level: (0, Good; 1, Moderate; 2, Poor; 3, Very poor); Absorption Level: (0, Good; 1, Moderate; 2, Poor; 3, Very poor); BBB Level: (0, very high blood–brain barrier penetration; 1, high; 2, medium; 3, low).