Synthesis and biological evaluation of 3-arylbenzofuranone derivatives as potential anti-Alzheimer’s disease agents

Figures & data

Scheme 1. General synthetic route to 3-arylbenzofuranone, reagents and conditions: (a) CHCl₃, TBAB, NaOH, 40–50 °C; (b) H₃O⁺; (c) BF₃·Et₂O, 30 °C.

Table 1. Compounds 1–23.

Product	R1	R2	R3	R4	R5	R6	R7
1	H	H	OCH3	H	H	OH	H
2	H	H	OCH3	H	H	H	OH
3	H	H	OCH3	H	H	OCH3	H
4	H	H	OCH3	H	H	H	OCH3
5	H	H	OCH3	H	OH	OH	H
6	H	OCH3	OCH3	H	H	OH	H
7	H	H	OCH3	H	H	OCH3	OH
8	H	H	OCH3	H	OH	OCH3	H
9	H	OCH3	OCH3	H	H	OCH3	H
10	H	H	OCH3	H	H	OCH3	OCH3
11	H	OCH3	OCH3	OCH3	H	OH	H
12	H	OCH3	OCH3	H	OH	OCH3	H
13	H	OCH3	OCH3	H	H	OCH3	OH
14	H	OCH3	OCH3	OCH3	H	H	OH
15	H	OCH3	OCH3	OCH3	H	H	OCH3
16	H	OCH3	OCH3	OCH3	H	OCH3	H
17	OCH3	OCH3	OCH3	H	H	H	OCH3
18	OCH3	OCH3	OCH3	H	H	OCH3	H
19	H	OCH3	OCH3	H	H	OCH3	OCH3
20	H	OCH3	OCH3	OCH3	OH	OH	H
21	H	OCH3	OCH3	OCH3	H	OCH3	OH
22	H	OCH3	OCH3	OCH3	OH	OCH3	H
23	H	OCH3	OCH3	OCH3	H	OCH3	OCH3

Table 2. Biological evaluation in vitro.

Product	IC50 value (μM)
	AChE inhibitory activity	BuChE inhibitory activity	MAO-B inhibitory activity	Antioxidant activity
1	50.58 ± 3.12	>200	61.26 ± 0.79	13.28 ± 0.27
2	4.15 ± 1.02	24.92 ± 0.96	14.67 ± 0.78	>100
3	80.48 ± 3.41	>200	298.43 ± 5.4	11.78 ± 0.18
4	0.74 ± 0.06	>200	383.45 ± 5.08	33.07 ± 1.45
5	0.48 ± 0.05	>200	22.48 ± 0.22	5.51 ± 0.20
6	24.38 ± 1.21	>200	48.59 ± 2.02	/
7	0.52 ± 0.07	32.92 ± 0.76	91.13 ± 0.70	2.62 ± 0.21
8	9.24 ± 0.62	>200	40.62 ± 1.92	5.96 ± 0.14
9	0.35 ± 0.03	>200	354.19 ± 5.05	17.17 ± 0.58
10	28.65 ± 1.44	>200	493.39 ± 7.10	13.89 ± 0.11
11	48.24 ± 0.34	>200	38.61 ± 0.42	11.22 ± 0.24
12	5.25 ± 0.44	180.91 ± 1.48	22.85 ± 0.73	1.60 ± 0.10
13	0.28 ± 0.01	9.91 ± 0.48	11.24 ± 0.72	5.33 ± 0.08
14	3.37 ± 0.17	128.33 ± 4.65	69.65 ± 1.26	5.11 ± 0.13
15	2.54 ± 0.19	>200	215.22 ± 2.27	32.58 ± 0.42
16	4.07 ± 0.19	>200	>500	18.01 ± 0.48
17	42.26 ± 4.01	>200	82.68 ± 1.31	29.17 ± 0.31
18	123.88 ± 2.17	>200	180.34 ± 1.32	64.48 ± 1.29
19	36.50 ± 0.51	>200	145.56 ± 1.83	12.56 ± 0.14
20	0.089 ± 0.01	>200	149.21 ± 3.39	42.56 ± 2.58
21	2.38 ± 0.20	145.89 ± 3.05	>500	5.35 ± 0.33
22	2.03 ± 0.09	>200	30.27 ± 0.65	6.44 ± 0.12
23	25.96 ± 1.26	>200	43.89 ± 1.26	11.94 ± 0.16
Donepezil	0.059 ± 0.003	4.67 ± 0.16
Rasagiline			0.104 ± 0.002
Ascorbic acid				7.69 ± 0.10

Each value represents the mean ± SD (n = 3).

Figure 1. Kinetic study of the mechanism of ChEs inhibition by compound 13. Overlaid Lineweaver–Burk reciprocal plots of ChEs initial velocity at increasing substrate concentration in the absence of inhibitor and in the presence of 13 are shown. A is a double reciprocal plot of compound 13 inhibition of AChE. B is a double reciprocal plot of compound 13 inhibition of BuChE.

Figure 2. Schematic presentations of the putative AChE binding modes with compound 20 and compound 11.

Figure 3. Schematic presentations of the putative BuChE binding modes with compound 13 and compound 19.

Figure 4. Schematic presentations of the putative MAO-B binding modes with compound 9 and compound 12.

Table 3. TOPKAT prediction results

Compound	Mutagenicity	TD50 value (mg/kg)		LD50 value(g/kg)
		Carcinogenicity (Mouse)	Carcinogenicity (Rat)	Acute oral toxicity (Rat)
1	0.495	184	7.9	0.719
2	0.535	184	7.9	0.998
3	0.631	89	1.49	0.784
4	0.586	89	2.08	1.95
5	0.569	83.6	7.11	0.842
6	0.406	252	11.8	2.62
7	0.583	209	5.81	0.488
8	0.571	127	5.81	0.732
9	0.522	100	2.09	2.89
10	0.528	100	2.09	1.62
11	0.211	268	6.87	1.76
12	0.522	268	8.55	1.83
13	0.533	268	8.55	1.75
14	0.274	268	9.24	1.37
15	0.323	106	1.64	1.76
16	0.33	106	2.08	1.73
17	0.443	106	2.08	3.63
18	0.474	106	1.49	1.73
19	0.516	128	2.19	2.75
20	0.293	198	6.11	2.59
21	0.336	158	3.89	1.07
22	0.292	282	8.46	1.95
23	0.275	75.4	0.994	1.67
Donepezil	0.22	99.8	1.56	0.392
Rasagiline	0.598	94.9	20.2	0.427