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

Figures & data

Figure 1. Donepezil (1) and reported donepezil analogues that function as AChE inhibitors.

Figure 2. Design strategy of the target compounds.

Scheme 1. The general route to prepare the α,β-unsaturated carbonyl compounds.

Scheme 2. Synthesis of the target benzyl pyridinium salts.

Table 1. AChE and BChE inhibition, ChEs selectivity, and K_i values for known and target compounds.

Compound	Chemical Structure	(IC50 ± SEM)^a		Selectivity Index (SI)^b (AChE)	(Ki ± SEM)a eeAChE (nM)
		AChE (nM)	BChE (μM)
Tacrine		30 ± 0.2	0.003 ± 0.047E-3	0.10	35 ± 0.013
Donepezil		14 ± 0.12	1.4 ± 0.043	101	27 ± 0.018
7a		32 ± 0.22	60 ± 0.096	19	39 ± 0.011
7b		52 ± 0.18	1.07 ± 0.080	21	56 ± 0.016
7c		280 ± 0.20	88 ± 0.104	3	−
7d		1120 ± 0.14	4.5 ± 0.073	4	−
7e		800 ± 0.12	3.9 ± 0.052	5	−
7f		7.5 ± 0.19	94 ± 0.063	55	6.0 ± 0.036
7 g		16 ± 0.18	1.04 ± 0.081	65	6.0 ± 0.031
7h		710 ± 0.16	6.36 ± 0.106	10	−
7i		220 ± 0.17	74 ± 0.110	3	−
7j		230 ± 0.19	1.4 ± 0.083	2	−
8a		56 ± 0.17	75 ± 0.069	14	102 ± 0.008
8b		54 ± 0.23	40 ± 0.079	7	90 ± 0.012
8c		1160 ± 0.17	61 ± 0.076	1	−
8d		630 ± 0.20	2.5 ± 0.079	4	−
8e		1500 0.22	2.7 ± 0.063	2	−
8f		17 ± 0.17	3.5 ± 0.095	473	16 ± 0.022
8 g		16 ± 0.24	1.2 ± 0.097	79	10 ± 0.025
8h		630 ± 0.22	1.8 ± 0.121	3	−
8i		270 ± 021	2.5 ± 0.100	11	−
8j		660 ± 0.21	9.8 ± 0.09	42	−

^aData are the mean ± standard error of three independent experiments that included duplicate samples.

^bSelectivity ratio [IC₅₀(BChE)/IC₅₀(AChE)].

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. Slopes of Lineweaver–Burk plots versus inhibitor 7a concentration.

Table 2. ABTS antioxidant activity.

	Inhibition %
	Concentrations (mg/mL)
Compounds	0.0312 mg/mL	0.0625 mg/mL	0.125 mg/mL	0.25 mg/mL	0.5 mg/mL
Trolox	9.3 ± 1.2	24.7 ± 1.2	51.0 ± 2.3	91.5 ± 1.8	93.9 ± 0.1
α-tocopherol	6.9 ± 2.3	15.9 ± 1.0	29.7 ± 1.3	56.4 ± 0.72	90.2 ± 0.04
7a	1.4 ± 0.56	1.5 ± 0.30	1.7 ± 0.68	3.5 ± 0.72	6.4 ± 0.47
7b	0.5 ± 0.47	1.4 ± 0.07	3.3 ± 0.10	6.2 ± 0.50	7.1 ± 0.59
8a	0.0 ± 0.70	0.3 ± 0.28	0.4 ± 0.36	1.4 ± 0.49	2.6 ± 0.38
8b	0.2 ± 0.40	0.3 ± 0.22	1.0 ± 0.52	2.3 ± 0.64	5.1 ± 0.62
7f	5.9 ± 0.47	13.7 ± 0.50	23.7 ± 0.51	35.5 ± 0.93	55.3 ± 1.42
7 g	6.1 ± 0.82	13.9 ± 0.68	22.5 ± 0.77	30.2 ± 1.86	52.1 ± 1.58
8f	7.7 ± 0.97	15.8 ± 0.18	25.4 ± 0.57	39.3 ± 0.23	59.1 ± 0.15
8 g	6.1 ± 0.71	13.7 ± 0.52	24.7 ± 0.51	39.5 ± 0.38	59.0 ± 0.71

Figure 5. Superposition of the X-ray (blue) and docked (light green) structures of donepezil within the active site of AChE.

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. Interaction mode of the target compound 7f in the active site of ACh.

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.