Design, synthesis and evaluation of new thiazole-piperazines as acetylcholinesterase inhibitors

Figures & data

Figure 1.  Structural motifs of AChE inhibitors BYYT-25, Donepezil, Acotiamide, and the synthesized compounds 5a–5p.

Table 1.  Some physicochemical characteristics of the synthesized compounds.

Compound	R	Yield (%)	M.p. (°C)	Molecular formula	Molecular weight
5a	Methyl	70	119	C17H22N4OS	330
5b	Ethyl	72	90	C18H24N4OS	344
5c	Cyclohexyl	75	128	C22H30N4OS	398
5d	Phenyl	80	160	C22H24N4OS	392
5e	4-Methylphenyl	81	172–175	C23H26N4OS	406
5f	4-Methoxyphenyl	73	180	C23H26N4O2S	422
5g	4-Chlorophenyl	75	176	C22H23ClN4OS	426.5
5h	4-Florophenyl	80	227	C22H23FN4OS	410
5i	4-Nitrophenyl	76	283–286	C22H23N5O3S	437
5j	3-Methylphenyl	72	190	C23H26N4OS	406
5k	3-Methoxyphenyl	74	143	C23H26N4O2S	422
5l	2-Methylphenyl	75	142	C23H26N4OS	406
5m	2-Methoxyphenyl	70	168	C23H26N4O2S	422
5n	2-Pyridyl	71	167	C21H23N5OS	393
5o	Benzyl	82	140	C23H26N4OS	406
5p	2-Furoyl	76	146	C21H22N4O3S	410

Scheme 1.  Synthesis of the compounds (5a–5p). Reagents: (i) acetyl chloride, TEA, THF, 0–5°C; (ii) Br₂, AcOH; (iii) thioacetamide, EtOH, r.t.; (iv) 1 N HCl, EtOH, reflux; (v) chloroacetyl chloride, TEA, THF, r.t.; (vi) appropriate 4-substituted piperazine, K₂CO₃, acetone, reflux.

Table 2.  Percentage AChE and BChE inhibition of the compounds and IC₅₀ values.

Comp.	AChE Inhibition (%)				BChE Inhibition (%)
	100 µM	1 µM	0.01 µM	IC50 (µM)	100 µM	1 µM	IC50 (µM)
5a	69.42 ± 5.09	41.26 ± 2.14	8.52 ± 0.18	7.12 ± 0.64	29.32 ± 3.41	6.13 ± 1.53	>100
5b	58.79 ± 6.44	38.24 ± 4.04	14.65 ± 1.26	11.74 ± 1.43	14.22 ± 2.16	4.81 ± 0.94	>100
5c	72.13 ± 9.26	40.29 ± 3.49	10.23 ± 0.96	6.34 ± 1.31	25.54 ± 4.32	8.75 ± 2.62	>100
5d	38.17 ± 4.21	19.24 ± 2.61	6.17 ± 1.11	>100	18.36 ± 0.87	4.43 ± 0.82	>100
5e	21.49 ± 3.22	16.42 ± 1.28	6.31 ± 1.34	>100	13.21 ± 1.63	8.62 ± 1.43	>100
5f	43.15 ± 5.89	22.70 ± 0.89	9.67 ± 0.72	>100	18.37 ± 1.44	3.56 ± 0.45	>100
5g	39.71 ± 5.27	18.47 ± 1.67	8.29 ± 2.07	>100	21.51 ± 2.96	6.31 ± 0.97	>100
5h	42.63 ± 2.64	19.06 ± 2.16	5.23 ± 0.49	>100	16.23 ± 1.84	7.14 ± 0.68	>100
5i	30.48 ± 4.25	14.28 ± 1.81	6.41 ± 1.34	>100	9.29 ± 2.45	2.24 ± 1.24	>100
5j	58.36 ± 7.34	27.42 ± 2.28	13.96 ± 2.16	88.35 ± 6.88	16.33 ± 1.47	7.24 ± 1.16	>100
5k	34.24 ± 2.51	11.74 ± 4.16	4.89 ± 1.44	>100	12.81 ± 1.61	5.41 ± 0.82	>100
5l	28.53 ± 4.81	12.24 ± 3.91	5.47 ± 0.28	>100	27.67 ± 2.12	8.03 ± 1.84	>100
5m	63.21 ± 7.26	39.53 ± 4.21	13.28 ± 1.55	8.42 ± 1.23	31.48 ± 4.93	13.07 ± 0.56	>100
5n	96.44 ± 5.21	84.96 ± 7.63	41.13 ± 3.47	0.051 ± 0.002	42.09 ± 5.16	18.89 ± 2.61	>100
5o	99.83 ± 4.42	87.70 ± 6.75	49.22 ± 4.57	0.011 ± 0.001	46.35 ± 5.08	21.12 ± 1.15	>100
5p	89.70 ± 6.37	63.61 ± 4.19	29.16 ± 1.84	0.27 ± 0.001	39.27 ± 1.19	14.69 ± 0.76	>100
Donepezil	96.82 ± 5.09	78.16 ± 5.43	36.26 ± 4.28	0.054 ± 0.002	71.56 ± 6.14	42.83 ± 3.23	7.18 ± 0.67