Structure–activity relationship investigation of benzamide and picolinamide derivatives containing dimethylamine side chain as acetylcholinesterase inhibitors

Figures & data

Figure 1. Comparison of chalcone derivatives and amide derivatives with diethanolamine side chain.

Scheme 1. Synthesis of benzamide derivatives. Reagents and conditions: (i) (COCl)₂, DCM, reflux;(ii) aminophenol, TEA, acetonitrile, 60 °C; (iii) (CH₃)₂N(CH₂)₂Cl₂, K₂CO₃, NaI, acetone, reflux.

Scheme 2. Synthesis of picolinamide amide derivatives. Reagents and conditions: (iv) aminophenol, DCC, HOBT, toluene, RT; (v) (CH₃)₂N(CH₂)₂Cl₂, K₂CO₃, NaI, acetone, reflux.

Table 1. Cholinesterase inhibitory activity and log p values of benzamide and picolinamide derivatives.

		IC50^a (μM) ± SD
Compound	Structure	AChE	BChE	Selectivity^b	Log p^c
4a		18.22 ± 1.16	142.94 ± 5.56	7.84	1.12
4b		75.79 ± 4.13	20.91 ± 1.61	0.276	1.18
4c		>500	17.96 ± 1.00	<0.0359	1.23
7a		2.49 ± 0.19	247.50 ± 7.54	99.4	1.26
7b		38.45 ± 2.19	48.55 ± 2.23	1.26	1.31
7c		>500	44.58 ± 1.16	<0.0892	1.37
7d		5.76 ± 0.41	246.51 ± 1.85	42.80	1.33
7e		13.25 ± 1.73	22.15 ± 1.01	1.67	1.37
7f		75.79 ± 0.84	33.41 ± 1.37	0.441	1.42
7g		4.68 ± 0.30	114.36 ± 7.73	24.4	1.14
7h		72.98 ± 3.03	35.91 ± 0.94	0.492	1.37
7i		>500	27.43 ± 2.31	<0.0549	1.18
Rivastigmine		10.5 ± 0.86	0.26 ± 0.08	0.0247	–

^a IC₅₀ values of compounds represent the concentration that caused 50% enzyme activity loss.

^b Selectivity for AChE is defined as IC₅₀ (BChE)/IC₅₀ (AChE).

^c The partition coefficients of in the octanol/buffer solution at pH 7.4 were determined by the classical shake-flask method.