Synthesis and biological evaluation of new Donepezil-like Thiaindanones as AChE inhibitors

Figures & data

Figure 1 Structure and anti-AChE activity of donepezil and thiaindanone derivatives 1-3.

Scheme 1 Synthesis of compounds 1 and 2. Reagents: (i) AcONH₄, CH₂(COOH)₂, EtOH; (ii) TFA₂O, Et₂O; (iii) Br₂, CH₂Cl₂; (iv) SOCl₂; (v) AlCl₃, CH₂Cl₂; (vi) HCl, H₂O, EtOH; (vii) TEA, BrCOCH₂Br, CH₂Cl₂; (viii) N-substituted benzylpiperazine, K₂CO₃, CH₂Cl₂.

Scheme 2 Synthesis of compounds 3,11-13. Reagents: (i) NH₂OH·HCl, AcONa, EtOH, H₂O; (ii) NaBH₄, MeOH; (iii) DAST, CH₂Cl₂; (iv) SOCl₂, CH₂Cl₂.

Scheme 3 Synthesis of compounds 14 and 15. Reagents: (i) NH₂·NH₂·xH₂0, MeOH; (ii) NCCH₂PO(OEt)₂, K₂CO₃, THF.

Scheme 4 Synthesis of compounds 16 and 17. Reagents: (i) a- Ph(CH₂)₅CO₂H, TEA, ClCO₂Et, CH₂Cl₂. b- 9, TEA, MeCN; (ii) a- 3-indolebutyric acid, TEA, ClCO₂Et, CH₂Cl₂. b- 9, TEA, MeCN.

Scheme 5 Synthesis of compound 19. Reagents: (i) TEA, BrCO(CH₂)₃Br, CH₂Cl₂; (ii) 1,2,3,4-tetrahydroisoquinoline, K₂CO₃, CH₂Cl₂.

Table I.  Anti-AChE activity of compounds 2, 3, 11-15..

Compound	R, R′	IC50 ± SD (μM)^a
2		0.40 ± 0.07 (n = 3)^b
3		0.06 ± 0.02 (n = 3)^b
11^c	H,OH	0.40 ± 0.10 (n = 3)^b
12^c	H, F	2.30 (n = 1)^b
13^c	H, Cl	0.63 ± 0.09 (n = 3)^b
14		1.50 ± 0.30 (n = 2)^b
15		>5.00

^a IC₅₀ value was measured for enzyme activity < 20% at 10^-5M^b n = number of duplicate independent experiments^c The value of the mixture (syn/anti) is shown

Table II.  Anti-AChE activity of compounds 1, 17, 18, 20..

Compound	IC50 ± SD (μM)^a
1	0.56 ± 0.05 (n = 3)^b
16	>5.00
17	>5.00
19	>5.00

^a IC₅₀ value was measured for enzyme activity < 20% at 10^{− 5} M^b n = number of duplicate independent experiments.