Synthesis and biological evaluation of novel flavonoid derivatives as dual binding acetylcholinesterase inhibitors

Figures & data

Scheme 1.  Reagent and conditions: (i) KOH, ethanol/water, rt, 10h (ii) NaOAc, 95% ethanol reflux 20h (iii) 3N HCl, methanol, 65°C, 0.5h (iv) PPh₃, DEAD, CH₂Cl₂, Et₃N, rt, 48h (v) I₂, pyridine, 90°C, 6h (vi) BzCl, DMF, 60°C, 3h (vii) a DIB-TsOH, methanol, rt, 4h b aq. NaOH, rt, 24h.

Table I.  AChE and BuChE inhibition data (IC₅₀, μM)^* of prepared compounds.

				IC50 (μM) ± SEM
Compound	R	n		AChE	BuChE
4a		0	p	7.6 ± 0.25	364 ± 23
4b		1	p	11.0 ± 0.1	75.3 ± 16
4c		0	m	12.7 ± 1.3	42.7 ± 1.2
4d		1	m	30.4 ± 0.37	573 ± 18
5a		0	p	4.05 ± 0.13	32.8 ± 2.7
5b		1	p	13.7 ± 0.34	835 ± 28
5c		0	m	6.58 ± 0.28	290 ± 31
5d		1	m	8.64 ± 0.46	783 ± 36
9a		0	p	0.093 ± 0.012	21.9 ± 3.1
9b		1	p	0.72 ± 0.04	25.9 ± 1.6
9c		0	m	1.29 ± 0.09	34.1 ± 0.4
9d		1	m	1.63 ± 0.23	19.3 ± 0.8
11a		0	p	20.4 ± 1.4	18.4 ± 4.5
11b		1	p	24.2 ± 1.1	672 ± 39
11c		0	m	inactive	385 ± 2.6
11d		1	m	inactive	43.6 ± 0.52
10a		0	p	inactive	inactive
10b		1	p	56.6 ± 1.9	inactive
10c		0	m	inactive	inactive
10d		1	m	inactive	inactive
donepezil				0.025 ± 0.003	4.57 ± 0.21

^* Data are means ± standard deviation of three independent experiments.

Figure 1.  Interaction between AChE and 9a.