Design, synthesis and preliminary structure–activity relationship investigation of nitrogen-containing chalcone derivatives as acetylcholinesterase and butyrylcholinesterase inhibitors: a further study based on Flavokawain B Mannich base derivatives

Figures & data

Scheme 1. Reagents and conditions: (a) benzaldehyde, NaOH, EtOH, rt; (b) Br(CH₂)_nBr, K₂CO₃, DMF, 80 °C; (c) secondary amine, K₂CO₃, NaI, acetone, reflux.

Table 1. Inhibition of AChE and BuChE (IC₅₀ values and selectivity) and log P values of nitrogen-containing chalcone derivatives.

			IC50^a (µmol/L)
Compound	R	n	AChE	BuChE	Selectivity for AChE^b	Log P^c
2			>500	>500	–	–
4a		2	33.23 ± 2.61	>500	>15.05	1.54
5a		3	127.12 ± 13.56	132.18 ± 10.03	1.04	1.70
6a		4	22.25 ± 1.02	>500	>22.47	1.73
7a		5	3.82 ± 0.23	18.56 ± 1.94	4.86	1.65
8a		6	5.54 ± 0.29	35.12 ± 7.13	6.34	1.63
4b		2	62.45 ± 3.72	34.26 ± 1.01	0.55	1.76
5b		3	97.47 ± 5.84	443.54 ± 11.20	4.55	1.79
6b		4	25.24 ± 1.33	66.16 ± 13.29	2.62	1.73
7b		5	1.50 ± 0.07	8.44 ± 0.85	5.63	1.69
8b		6	4.41 ± 0.36	27.57 ± 1.86	6.25	1.81
4c		2	25.61 ± 2.12	43.47 ± 2.33	1.70	1.84
5c		3	33.34 ± 0.89	16.01 ± 0.18	0.48	1.79
6c		4	0.85 ± 0.04	30.42 ± 1.71	35.79	1.77
7c		5	2.98 ± 0.21	1.95 ± 0.08	0.65	1.89
8c		6	3.64 ± 0.22	2.19 ± 0.75	0.60	1.92
4d		2	17.36 ± 1.28	2.77 ± 0.03	0.16	1.88
5d		3	33.32 ± 1.64	77.88 ± 7.81	2.34	1.86
6d		4	1.42 ± 0.09	31.24 ± 0.60	22.00	1.95
7d		5	2.48 ± 0.11	4.49 ± 0.17	1.81	1.98
8d		6	3.46 ± 0.24	8.24 ± 1.02	2.38	1.94
Rivastigmine			10.54 ± 0.86	0.26 ± 0.08	0.02	1.68

^aIC₅₀ value: 50% inhibitory concentration (means ± SD of three experiments).

^bSelectivity for AChE is defined as IC₅₀ (BuChE)/IC₅₀ (AChE).

^cThe partition coefficients between octanol and buffer solution at pH 7.4 were determined by the classical shake-flask method.

Figure 1. (A) Effects of alkyl chain lengths on anti-AChE activities; (B) effects of alkyl chain lengths on selectivity for AChE.

Figure 2. The comparison of the inhibitory activity between the corresponding Flavokawain B derivatives and chalcone derivatives against AChE.

Figure A1. Some examples of the derivatives from natural products with structural simplification.

Figure A2. (A) Lineaweaver–Burk plot for the inhibition of AChE by compound 6c; (B) the replots of the intercept versus concentration of compound 6c; (C) the replots of the slope versus concentration of compound 6c.

Figure A3. Molecular modelling of compound 6c with AChE (A) and BuChE (B) generated with MOE2008.

Table A1. Kinetic parameters of AChE inhibition by compound 6c.

6c/µmol/L	Michaelis–Menten equation	Km/mmol/L	Vmax/ΔA/min	Ki/µmol/L	Ki^’/µmol/L
0	1/v = 191.67/[S] + 37.94	5.051	0.0264
0.58	1/v = 353.16/[S] + 54.60	6.467	0.0183	0.69	1.19
1.16	1/v = 514.20/[S] + 74.43	6.908	0.0134