Synthesis and biological evaluation of aminomethyl and alkoxymethyl derivatives as carbonic anhydrase, acetylcholinesterase and butyrylcholinesterase inhibitors

Figures & data

Figure 1. The hydrolyze reaction of acetylcholine in the presence of acetylcholinesterase enzyme (AChE).

Table 1. Physico-chemical characteristics of aminomethyl derivatives of benzothiazol- and benzoxazolthiones

				Found/calculated (%)
No	Compound	The melting point (°C)	Yield (%)	C	H	N	S	Brutto formula	NMR spectra δ (ppm)
1		120–121	45	54.61 54.13	5.76 5.26	10.60 10.52	24.20 24.06	C12H14N2OS2	1.79 (kv. 2H, CH2CH2CH2), 3.29(t., 2H, NCH2), 3.9 (t., 2H, ОCH2), 4.567 (t., 2H, NCH2N), 5.3 (s., 2H, NCH2O), 6.8–7.6 (m., 4H, C6H4).
2		124–126	40	56.00 57.60	5.90 5.30	10.30 10.50	26.60 24.60	C11H12N2OS2	1.819 (kv. 2H, CH2CH2CH2), 3.119 (t., 2H, NCH2), 3.9 (t., 2H, ОCH2), 4.567 (t., 2H, NCH2N), 5.3 s. 2H (NCH2O), 7.1–7.3 m. 4H (C6H4)
3		134	40	54.9 54.13	5.55 5.26	11.01 10.52	24.56 24.06	C12H14N2OS2	1.7 (m., 2H, CH2CH2CH2), 1.97 (m., 4H, CH2CH2CH2), 3.01 (t., 4H, NCH2N), 7.6–8.9 (d., 4H, C5-C7), 8.1 (s., 2H, ArCH2N).
4		152–152.5	42	57.6 57.0	7.5 5.6	11.3 11.2	28.8 25.6	C13H16N2S2	1.5 (m., 2H, CH2CH2CH2), 1.7 (m., 4H, CH2CH2CH2), 3.15 (t., 4H, NCH2N), 7.1–7.6 (d., 4H, C5-C7), 8 (s., 2H, ArCH2N).
5		128–130	35	54.4 57.14	5.98 6.35	8.2 11.11	27.0 25.4	C12H16N2S2	2.19 (kv, 2H, CH2CH2CH2), 3.12 (t., 2H, NCH2), 3.6 (t., 2H, ОCH2), 4.67 (t., 2H, NCH2N), 5.20 s. 2H (NCH2O), 7.1–7.5 m. 4H (C6H4).
6		105	65	59.87 61.02	5.98 6.78	10.85 11.86	13.03 13.56	C12H16N2OS	1.28 (m., 2H, CH2CH2CH2), 3.04 (t., 2H, CH2N), 3.69 t., (2H, CH2О), 4.59 (s., 2H, NCH2N), 5.36 (s., 2H, NCH2O), 6.9–7.9 (m., 4H, C6H4).
7		125	45	63.52 62.9	6.04 6.45	9.39 11.29	11.53 12.9	C13H16N2OS	1.88 (m., 2H, CH2CH2CH2), 3.18 (t., 2H, CH2N), 3.9 (t., 2H, CH2О), 4.39 (s., 2H, NCH2N), 5.56 (s. 2H, NCH2O), 7.4–7.7 (m., 4H, C6H4).
8		145–147	48	57.58 57.6	5.7 5.6	11.34 11.2	12.54 12.8	C12H14N2O2S	1.21 (d., 2H, CH2CH2CH2), 3.23 (t., 2H, CH2N), 3.7 (t., 2H, CH2О), 4.39 (s., 2H, NCH2N), 5.86 (s., 2H, NCH2O), 7.14–7.97 (m., 4H, C6H4).
9		115–118	60	55.84 55.93	5.25 5.08	11.65 11.86	13.87 13.55	C11H12N2O2S	1.38 (m., 2H, CH2CH2CH2), 2.08 (t. 2H, CH2N), 3.39 (t., 2H, CH2О), 3.59 (s., 2H, NCH2N), 5.16 (s., 2H, NCH2O), 7.1–8.7 (m., 4H, C6H4).
10		145–147	67.6	56.0 57.6	5.51 5.6	11.0 11.2	13.3 12.8	C12H14N2O2S	1.8 (m., 2H, CH2CH2CH2), 3.08 (t., 2H, CH2N), 3.9 (t., 2H, CH2О), 4.59 (s., 2H, NCH2N), 5.56 (s.,. 2H, NCH2O), 7.4–7.7 (m., 4H, C6H4).

Table 2. Physico-chemical characteristics of the alkoxymethyl derivatives of benzoxazolthione and 2-aminothiazoles.

				Found/calculated (%)
No	Compounds	Melting point (°C)	Yield (%)	C	H	N	S	Brutto Formula	NMR spectra δ (ppm)
11		130	71.72	55.40 55.38	4.58 4.61	7.13 7.18	16.35 16.41	C9H9NO2S	2.06 (s., 3H, OCH3); 5.781 (s., 2H, NCH2O); 7.373–7.55 (m., 4H, C6H6).
12		132–133	77	57.37 57.42	5.15 5.26	6.64 6.70	15.23 15.31	C10H11NO2S	2.06–2.096 (t., 3H, CH3); 3.07 (kv, 2H,CH2CH3); 5.766 (s., 2H, NCH2O); 7.33–7.52 (m., 4H, C6H4).
13		126–127	24	57.33 57.42	5.63 5.83	6.13 6.28	14.18 14.35	C11H13NO2S	2.01–2.16 (d., 6H, (CH3)2; 2.999 (m., 1H, OCH); 5.77 (s., 2H, NCH2O); 7.34–7.53 m., 4H, C6H4).
14		120–121	19	55.17 55.23	5.35 5.44	5.75 5.86	13.28 13.39	C11H13NO3S	1.06-2.01 (t., 3H, CH3), 3.072 (kv, 2H,CH2CH3), 5.62 (s., 2H, NCH2O), 6.83–7.92 (m., 4H, C6H4).
15		120–121	30	43.52 44.68	6.28 6.38	14.78 14.89	17.15 17.02	C7H12N2SO2	2.86 (s., 1H, NH); 5.11 (t., 4H,-OCH2CH2O-); 5.29 s. (3H, -OCH3); 5.20 (s., 2H, NCH2O); 6.86 (d., 1H, SCH); 7.61 (d., 1H, NCH).
16		118–120	–	47.98 48.84	6.35 6.98	15.97 16.28	17.80 18.6	C7H12N2SO	1.11-2.10 (t., 3H, CH3), 3.10 (kv, 2H,CH2CH3), 5.20 (s., 2H, NCH2O), 6.83–7.792 (m., 4H, C6H4).
17		126–127	27	40.52 41.67	5.03 5.56	18.37 19.44	23.12 22.22	C5H8N2SO	2.86–2.47 (s., 1H, NH); 5.19 (t., 4H, -OCH2CH2O-); 5.19 s. (3H, -OCH3); 5.12 (s., 2H, NCH2O); 6.68 (d., 1H, SCH); 7.71 (d., 1H, NCH).

Table 3. AChE, human carbonic anhydrase I, and II isoforms (hCA I, and II) AChE and BChE enzymes inhibition effects of aminomethyl and alkoxymethyl derivatives (1–17) and proportion of AChE to BChE enzymes.

	IC50 (nM)								Ki (nM)
Compounds	hCA I	r^2	hCA II	r^2	AChE	r^2	BChE	r^2	hCA I	hCA II	AChE	BChE	AChE/BChE
1	79	0.9639	104	0.9527	51	0.9762	88	0.9964	108 ± 35	81 ± 19	26 ± 5	32 ± 7	0.812
2	79	0.9852	114	0.9839	39	0.9885	89	0.9773	77 ± 15	107 ± 11	33 ± 5	51 ± 4	0.647
3	83	0.9597	89	0.9555	54	0.9670	75	0.9619	106 ± 39	96 ± 22	37 ± 11	45 ± 9	0.822
4	86	0.9588	99	0.9774	36	0.9855	82	0.9630	86 ± 40	105 ± 25	18 ± 2	41 ± 13	0.439
5	82	0.9755	98	0.9670	52	0.9699	83	0.9359	70 ± 15	100 ± 24	34 ± 9	51 ± 9	0.666
6	102	0.9359	118	0.9649	44	0.9857	80	0.9750	123 ± 48	115 ± 28	45 ± 11	30 ± 3	1.500
7	79	0.9597	116	0.9457	65	0.9874	79	0.9520	82 ± 17	132 ± 27	40 ± 8	57 ± 17	0.701
8	94	0.9533	119	0.9619	38	0.9848	48	0.9911	58 ± 15	121 ± 40	32 ± 6	23 ± 3	1.391
9	103	0.9652	121	0.9440	62	0.9769	84	0.9904	76 ± 20	135 ± 33	78 ± 36	80 ± 9	0.975
10	98	0.9550	137	0.9452	50	0.9819	94	0.9710	99 ± 22	135 ± 42	61 ± 9	50 ± 10	1.220
11	112	0.9607	172	0.9711	89	0.9865	133	0.9621	118 ± 40	137 ± 35	45 ± 5	77 ± 17	0.584
12	119	0.9752	141	0.9695	63	0.9908	93	0.9947	95 ± 25	146 ± 46	75 ± 8	88 ± 11	0.852
13	105	0.9664	122	0.9483	63	0.9859	83	0.9807	90 ± 23	94 ± 37	34 ± 5	35 ± 4	0.971
14	112	0.9426	128	0.9556	38	0.9860	68	0.9704	119 ± 53	142 ± 56	23 ± 4	60 ± 13	0.383
15	128	0.9783	158	0.9644	43	0.9888	109	0.9752	118 ± 27	193 ± 79	25 ± 3	45 ± 14	0.555
16	156	0.9757	167	0.9659	76	0.9949	127	0.9590	132 ± 30	162 ± 29	42 ± 4	55 ± 12	0.763
17	142	0.9774	187	0.9562	80	0.9912	144	0.9749	157 ± 38	215 ± 40	54 ± 10	42 ± 20	1.285
AZA^a	373	0.9774	520	0.9816	—	—	—	—	333 ± 28	353 ± 60	—	—	—
TAC^b	—	—	—	—	174	0.9513	280	0.9879	—	—	109 ± 5	128 ± 16	0.851

Tacrine (TAC) was used as a standard inhibitor for BChE and AChE enzymes.

^a Acetazolamide (AZA) was used as a standard inhibitor for both carbonic anhydrase I, and II isoenzymes (hCA I and II).

Figure 2. (a) IC₅₀ values of aminomethyl and alkoxymethyl derivatives for hCA I, and II isoenzymes. (b) IC₅₀ values of aminomethyl and alkoxymethyl derivatives for AChE and BChE enzymes. (c) K_i values of aminomethyl and alkoxymethyl derivatives for hCA I, and II isoenzymes. (d) K_i values of aminomethyl and alkoxymethyl derivatives for AChE and BChE enzymes.