Design, synthesis and biological activity of 1H-indene-2-carboxamides as multi-targeted anti-Alzheimer agents

Figures & data

Figure 1. Structures of some AChE inhibitors: donepezil and indanol- and indene-based derivatives (I and II) reported as AChE inhibitors.

Scheme 1. Reagents and conditions: (a) oxalyl chloride, CH₂Cl₂, room temperature, 12 h; (b) AlCl₃, CH₂Cl₂, 0 °C, ice bath; (c) Dimethyl carbonate, NaH, 90 °C, reflux; (d) appropriate aniline, dioxane, microwave; (e) NaBH4, THF, MeOH, 2 h; (f) MeOH, PTSA, reflux, 25 min. *R₁, R₂, R₃ substituent groups at the o-, m- and p- positions: H, CH₃, C₂H₅, OCH₃, OC₂H₅, F, Cl and Br.

Table 1. Anticholinesterase activity, inhibition of self-induced Aβ_1–42 aggregation of the compounds (1–22).

Compound	R^1	R^2	R^3	IC50 (μM)±SD^§		Selectivity for BuChE^‡	Aβ1–42 aggregation inhibition¶,§ (%)	Log P^‖	MR^‖
				AChE*,§	BuChE†,§
1	H	H	H	6.42 ± 1.685	1.23 ± 0.125	5.2	34.6 ± 0.1	2.85	86.89
2	CH3	H	H	4.17 ± 0.207	1.45 ± 0.07	2.9	40.3 ± 1.4	3.34	92.78
3	C2H5	H	H	5.16 ± 3.158	1.48 ± 0.12	3.5	31.5 ± 2.5	3.75	97.38
4	OCH3	H	H	6.47 ± 0.33	5.07 ± 0.103	1.3	5.4 ± 0.7	2.72	94.14
5	OC2H5	H	H	5.27 ± 0.127	3.78 ± 0.042	1.4	9.8 ± 1.9	3.06	98.94
6	F	H	H	3.69 ± 0.08	1.38 ± 0.012	2.7	42.5 ± 2.2	3.01	87.29
7	Cl	H	H	3.85 ± 0.141	2.8 ± 0.41	1.4	30.3 ± 3.7	3.41	91.49
8	Br	H	H	3.17 ± 0.105	2.64 ± 0.01	1.2	33.4 ± 1.1	3.68	94.58
9	H	CH3	H	4.45 ± 0.197	2.05 ± 0.059	2.2	12.7 ± 1.3	3.34	92.78
10	H	C2H5	H	4.63 ± 0.007	4.9 ± 0.47	0.9	8.4 ± 2.7	3.75	97.38
11	H	OCH3	H	4.5 ± 0.197	3.05 ± 0.112	1.5	13.8 ± 1.5	2.72	94.14
12	H	OC2H5	H	5.87 ± 1.332	2.41 ± 0.19	2.4	22.6 ± 2.7	3.06	98.94
13	H	F	H	2.86 ± 0.172	2.23 ± 0.121	1.3	26.9 ± 1.0	3.01	87.29
14	H	Cl	H	2.29 ± 0.574	3.49 ± 0.068	0.7	10.1 ± 2.8	3.41	91.49
15	H	Br	H	4.34 ± 0.10	5.57 ± 0.27	0.8	3.8 ± 3.1	3.68	94.58
16	H	H	CH3	3.51 ± 0.022	1.28 ± 0.059	2.7	46.4 ± 4.0	3.34	92.78
17	H	H	C2H5	3.50 ± 3.568	1.72 ± 0.13	2.0	37.6 ± 0.3	3.75	97.38
18	H	H	OCH3	3.95 ± 0.06	3.71 ± 0.125	1.1	14.8 ± 2.7	2.72	94.14
19	H	H	OC2H5	4.87 ± 0.038	4.32 ± 0.072	1.1	11.3 ± 3.1	3.06	98.94
20	H	H	F	2.33 ± 0.021	1.08 ± 0.011	2.2	50.3 ± 2.4	3.01	87.29
21	H	H	Cl	1.33 ± 0.062	1.27 ± 0.032	1.0	45.7 ± 3.5	3.41	91.49
22	H	H	Br	3.02 ± 0.072	1.09 ± 0.31	2.8	48.2 ± 0.8	3.68	94.58
Donepezil				0.042 ± 0.041	0.54 ± 0.017	0.1
Curcumin							42.3 ± 2.6

*50% Inhibitory concentration of AChE.

†50% Inhibitory concentration of BuChE.

‡Selectivity for BuChE = IC₅₀ (AChE)/IC₅₀ (BuChE).

¶Inhibition of self-induced Aβ_1–42 aggregation (25 μM) by tested inhibitors (25 μM).

§Values are expressed as mean ± standart error of the mean of three independent experiments and each performed in triplicate (SD = standart deviation).

‖ Calculated by ChemDraw 2015.

MR: Molar Refractivity.

Figure 2. Lineweaver–Burk plots of inhibition kinetics of the compounds 20 and 21.

Figure 3. Inhibition of self-induced Aβ_1–42 aggregation by the test compounds and reference curcumin at concentration 25 μM.

Figure 4. (a) UV absorption spectra of compound 20 (100 μM in DMSO) alone, (b) UV absorption spectra of the mixture compound 20 (100 μM) and CuSO₄ (100 μM), (c) UV absorption spectra of the mixture compound 20 (100 μM) and FeSO₄ (100 μM) and (d) UV absorption spectra of the mixture compound 20 (100 μM) and ZnSO₄ (100 μM).

Figure 5. 3D representation of the binding mode of the most potent inhibitor 21 at the active sites of AChE.

Figure 6. 3D representation of the binding mode of the most potent inhibitor 20 at the active sites of BuChE.