yntheses and Anti-cholinesterase Activity of 4-N-Phenylaminoquinoline Derivatives †

doi:10.7503/cjcu20160880

Abstract

Abstract:

A series of 4-N-Phenylaminoquinoline derivatives was designed and synthesized, and their anti-cholinesterase activities were evaluated using Ellman assay. The results demonstrated that the stretched-out quaternary pyridine in quinoline ring greatly improved the cholinesterase inhibition of target compounds. Compound 16 exhibited the most potent inhibitory activities against both acetylcholinesterase(AChE) and butyrylcholinesterase(BChE) from the prepared series, with IC₅₀ values of 0.92 and 14.20 μmol/L, respectively, which showed superior activitities compared with the reference drug galanthamine. These results suggest that compound 16 may be valuable as a new parent compound for further structural modifications.

Key words: 4-N-Phenylaminoquinoline derivatives, Anti-cholinesterase activity, Structure-activity relationship(Ed.: P, H, F, K)

CLC Number:

O626.32

TrendMD:

LIU Yuming, TIAN Lijun, HU Dong, NIE Jianbing. yntheses and Anti-cholinesterase Activity of 4-N-Phenylaminoquinoline Derivatives ^†[J]. Chem. J. Chinese Universities, 2017, 38(3): 392.

Figures/Tables 4

References 40

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	S

Compd.	Appearance	Yield(%)	m. p./℃	HR-ESI-MS(Calcd.), m/z
6a	Yellow solid	82.3	274—276(274—276^[37])	255.0743(255.0689)[M+H]⁺
6b	Yellow solid	86.4	280—283(279—281^[37])	269.0888(269.0846)[M+H]⁺
6c	Slightly yellow solid	78.0	297—299(298—299^[37])	271.0679(271.0638)[M+H]⁺
6d	Slightly yellow solid	75.1	>300(303—305^[37])	271.0683(271.0638)[M+H]⁺
6e	White solid	56.1	241—243(241—243^[37])	289.0342(289.0299)[M+H]⁺
6f	White solid	80.9	261—263(261—262^[37])	289.0343(289.0299)[M+H]⁺
6g	Slightly yellow solid	75.2	292—294(292—293^[37])	289.0320(289.0299)[M+H]⁺
6h	White solid	50.2	>300	322.9936(322.9910)[M+H]⁺
6i	White solid	43.4	>300	319.0454(319.0405)[M+H]⁺
6j	White solid	42.9	>300	353.0038(353.0015)[M+H]⁺
7	White solid	88.4	61—63(63—64^[38])	181.0505(181.0501)[M-H]^-
8	White solid	79.2	100—102(99—100^[39])
9	Yellow solid	86.2	65—67(66—68^[39])	326.0403(326.0407)[M+Na]⁺
10	White solid	87.4	98—99(97—98^[39])	274.0858(274.0846)[M+H]⁺
11	White solid	82.0	165—166(164—165^[40])	258.0535(258.0533)[M-H]^-
12	Yellow solid	83.1	184—186	329.0545(329.0540)[M-H]^-
13	Grey-white solid	30.9	270—272	313.0594(313.0591)[M+H]⁺
14	Grey-white solid	88.6	121—123	331.0260(331.0252)[M+H]⁺
15	Yellow solid	74.5	169—171	422.0691(422.0674)[M+H]⁺
16	Red solid	66.7	229—232	465.1364(465.1330)[M-Cl]⁺
17	Yellow solid	77.8	163—165	435.1586(435.1588)[M-Cl]⁺

Compd.	Appearance	Yield(%)	m. p./℃	HR-ESI-MS(Calcd.), m/z
6a	Yellow solid	82.3	274—276(274—276^[37])	255.0743(255.0689)[M+H]⁺
6b	Yellow solid	86.4	280—283(279—281^[37])	269.0888(269.0846)[M+H]⁺
6c	Slightly yellow solid	78.0	297—299(298—299^[37])	271.0679(271.0638)[M+H]⁺
6d	Slightly yellow solid	75.1	>300(303—305^[37])	271.0683(271.0638)[M+H]⁺
6e	White solid	56.1	241—243(241—243^[37])	289.0342(289.0299)[M+H]⁺
6f	White solid	80.9	261—263(261—262^[37])	289.0343(289.0299)[M+H]⁺
6g	Slightly yellow solid	75.2	292—294(292—293^[37])	289.0320(289.0299)[M+H]⁺
6h	White solid	50.2	>300	322.9936(322.9910)[M+H]⁺
6i	White solid	43.4	>300	319.0454(319.0405)[M+H]⁺
6j	White solid	42.9	>300	353.0038(353.0015)[M+H]⁺
7	White solid	88.4	61—63(63—64^[38])	181.0505(181.0501)[M-H]^-
8	White solid	79.2	100—102(99—100^[39])
9	Yellow solid	86.2	65—67(66—68^[39])	326.0403(326.0407)[M+Na]⁺
10	White solid	87.4	98—99(97—98^[39])	274.0858(274.0846)[M+H]⁺
11	White solid	82.0	165—166(164—165^[40])	258.0535(258.0533)[M-H]^-
12	Yellow solid	83.1	184—186	329.0545(329.0540)[M-H]^-
13	Grey-white solid	30.9	270—272	313.0594(313.0591)[M+H]⁺
14	Grey-white solid	88.6	121—123	331.0260(331.0252)[M+H]⁺
15	Yellow solid	74.5	169—171	422.0691(422.0674)[M+H]⁺
16	Red solid	66.7	229—232	465.1364(465.1330)[M-Cl]⁺
17	Yellow solid	77.8	163—165	435.1586(435.1588)[M-Cl]⁺

Compd.	¹H NMR(400 MHz), δ	¹³C NMR(100 MHz), δ
6h	6.50(d, J=6.9 Hz, 1H), 7.59(br s, 2H), 7.79(br s, 1H), 7.83(dd, J=2.0, 9.1 Hz, 1H), 8.04(d, J=2.0 Hz, 1H), 8.46(d, J=6.9 Hz, 1H), 8.61(d, J=9.1 Hz, 1H)	103.2, 118.1, 118.6, 121.8, 127.2, 130.5, 131.3, 132.7, 132.9, 135.2, 137.4, 141.6, 142.6, 145.7, 158.5
6i	3.80(s, 3H), 6.34(d, J=6.9 Hz, 1H), 7.12(dd, J=3.0, 9.0 Hz, 1H), 7.22(d, J=3.0 Hz, 1H), 7.62(d, J=9.0 Hz, 1H), 7.88(dd, J=2.0, 9.1 Hz, 1H), 8.28(d, J=2.0 Hz, 1H), 8.57(d, J=6.9 Hz, 1H), 8.99(d, J=9.1 Hz, 1H), 11.46(br s, 1H, NH)	56.4, 101.4, 115.4, 116.0, 116.4, 119.7, 122.5, 126.7, 128.1, 131.7, 135.2, 139.0, 139.4, 143.8, 155.7, 159.7
6j	3.85(s, 3H), 6.28(br s, 1H), 7.26(s, 1H), 7.61(d, J=8.5 Hz, 1H), 7.77(s, 1H), 7.91(br s, 1H), 8.42(br s, 1H), 8.47(d, J=8.5 Hz, 1H)	57.2, 102.8, 112.9, 118.2, 119.9, 122.0, 125.2, 125.9, 126.5, 131.0, 135.1, 137.6, 148.0, 150.0, 150.6, 154.9
12	2.21(m, 2H), 3.78(s, 3H), 3.79(t, J=6.4 Hz, 2H), 4.22(t, J=5.9 Hz, 2H), 6.66(d, J=6.1 Hz, 1H), 7.25(s, 1H), 7.53(s, 1H), 8.02(dd, J=6.1, 13.2 Hz, 1H), 13.93(d, J=13.2 Hz, 1H)	31.6, 41.9, 55.9, 65.7, 100.2, 108.4, 112.7, 113.4, 136.2, 138.2, 144.9, 153.1, 168.1
13	2.27(m, 2H), 3.82(t, J=6.4 Hz, 2H), 3.90(s, 3H), 4.21(t, J=6.1 Hz, 2H), 7.19(s, 1H), 7.60(s, 1H), 9.08(s, 1H)	31.4, 41.8, 55.8, 65.5, 101.9, 105.4, 122.2, 130.4, 134.5, 140.7, 148.1, 152.4, 166.6
14	2.29(m, 2H), 3.83(t, J=6.4 Hz, 2H), 4.02(s, 3H), 4.36(t, J=5.9 Hz, 2H), 7.52(s, 1H), 7.58(s, 1H), 9.17(s, 1H)	31.4, 41.8, 56.3, 65.9, 102.9, 109.0, 120.4, 132.6, 139.8, 142.7, 146.4, 152.1, 154.2
15	2.26(m, 2H), 3.78( s, 3H), 3.81(t, J=6.4 Hz, 2H), 4.28(t, J=5.8 Hz, 2H), 7.08(d, J=8.6 Hz, 2H), 7.36(d, J=8.6 Hz, 2H), 7.39(s, 1H), 7.56(s, 1H), 8.94(s, 1H), 9.80(s, 1H, NH)	31.9, 42.3, 56.3, 65.8, 104.1, 109.9, 115.4, 122.0(2C), 128.0, 129.5(2C), 130.3, 141.0, 141.2, 144.9, 146.9, 149.7, 153.3
16	2.56(m, 2H), 3.73( s, 3H), 4.36(t, J=5.4 Hz, 2H), 4.86(t, J=6.2 Hz, 2H), 7.10(d, J=8.6 Hz, 2H), 7.34(d, J=8.6 Hz, 2H), 7.38(s, 1H), 7.78(s, 1H), 8.14(t-like, J=6.9 Hz, 2H), 8.63(t, J=7.8 Hz, 1H), 8.92(s, 1H), 9.17(d, J=5.8 Hz, 2H), 10.12(s, 1H, NH)		30.0, 56.5, 59.7, 66.9, 104.4, 109.8, 115.9, 121.5(2C), 127.6, 128.4(2C), 129.4(2C), 130.3, 140.9, 141.2, 145.0, 145.5(2C), 145.8, 146.8, 149.5, 152.8
17	2.69(m, 2H), 3.68( s, 3H), 4.40(t, J=5.4 Hz, 2H), 4.97(t, J=6.6 Hz, 2H), 6.97(d, J=8.0 Hz, 2H), 7.17(s, 1H), 7.32(s, 1H),7.34(d, J=8.0 Hz, 2H), 8.14(t-like, J=6.6 Hz, 2H), 8.31(s, 1H), 8.65(t, J=7.7 Hz, 1H), 9.14(d, J=5.6 Hz, 2H)		29.8, 54.8, 59.7, 66.4, 101.2, 102.4, 118.6, 119.5(2C), 126.4, 128.0, 128.1(2C), 128.6(2C), 130.0, 131.1, 132.7, 140.5, 145.0(2C), 145.4, 150.1, 150.5

Compd.	¹H NMR(400 MHz), δ	¹³C NMR(100 MHz), δ
6h	6.50(d, J=6.9 Hz, 1H), 7.59(br s, 2H), 7.79(br s, 1H), 7.83(dd, J=2.0, 9.1 Hz, 1H), 8.04(d, J=2.0 Hz, 1H), 8.46(d, J=6.9 Hz, 1H), 8.61(d, J=9.1 Hz, 1H)	103.2, 118.1, 118.6, 121.8, 127.2, 130.5, 131.3, 132.7, 132.9, 135.2, 137.4, 141.6, 142.6, 145.7, 158.5
6i	3.80(s, 3H), 6.34(d, J=6.9 Hz, 1H), 7.12(dd, J=3.0, 9.0 Hz, 1H), 7.22(d, J=3.0 Hz, 1H), 7.62(d, J=9.0 Hz, 1H), 7.88(dd, J=2.0, 9.1 Hz, 1H), 8.28(d, J=2.0 Hz, 1H), 8.57(d, J=6.9 Hz, 1H), 8.99(d, J=9.1 Hz, 1H), 11.46(br s, 1H, NH)	56.4, 101.4, 115.4, 116.0, 116.4, 119.7, 122.5, 126.7, 128.1, 131.7, 135.2, 139.0, 139.4, 143.8, 155.7, 159.7
6j	3.85(s, 3H), 6.28(br s, 1H), 7.26(s, 1H), 7.61(d, J=8.5 Hz, 1H), 7.77(s, 1H), 7.91(br s, 1H), 8.42(br s, 1H), 8.47(d, J=8.5 Hz, 1H)	57.2, 102.8, 112.9, 118.2, 119.9, 122.0, 125.2, 125.9, 126.5, 131.0, 135.1, 137.6, 148.0, 150.0, 150.6, 154.9
12	2.21(m, 2H), 3.78(s, 3H), 3.79(t, J=6.4 Hz, 2H), 4.22(t, J=5.9 Hz, 2H), 6.66(d, J=6.1 Hz, 1H), 7.25(s, 1H), 7.53(s, 1H), 8.02(dd, J=6.1, 13.2 Hz, 1H), 13.93(d, J=13.2 Hz, 1H)	31.6, 41.9, 55.9, 65.7, 100.2, 108.4, 112.7, 113.4, 136.2, 138.2, 144.9, 153.1, 168.1
13	2.27(m, 2H), 3.82(t, J=6.4 Hz, 2H), 3.90(s, 3H), 4.21(t, J=6.1 Hz, 2H), 7.19(s, 1H), 7.60(s, 1H), 9.08(s, 1H)	31.4, 41.8, 55.8, 65.5, 101.9, 105.4, 122.2, 130.4, 134.5, 140.7, 148.1, 152.4, 166.6
14	2.29(m, 2H), 3.83(t, J=6.4 Hz, 2H), 4.02(s, 3H), 4.36(t, J=5.9 Hz, 2H), 7.52(s, 1H), 7.58(s, 1H), 9.17(s, 1H)	31.4, 41.8, 56.3, 65.9, 102.9, 109.0, 120.4, 132.6, 139.8, 142.7, 146.4, 152.1, 154.2
15	2.26(m, 2H), 3.78( s, 3H), 3.81(t, J=6.4 Hz, 2H), 4.28(t, J=5.8 Hz, 2H), 7.08(d, J=8.6 Hz, 2H), 7.36(d, J=8.6 Hz, 2H), 7.39(s, 1H), 7.56(s, 1H), 8.94(s, 1H), 9.80(s, 1H, NH)	31.9, 42.3, 56.3, 65.8, 104.1, 109.9, 115.4, 122.0(2C), 128.0, 129.5(2C), 130.3, 141.0, 141.2, 144.9, 146.9, 149.7, 153.3
16	2.56(m, 2H), 3.73( s, 3H), 4.36(t, J=5.4 Hz, 2H), 4.86(t, J=6.2 Hz, 2H), 7.10(d, J=8.6 Hz, 2H), 7.34(d, J=8.6 Hz, 2H), 7.38(s, 1H), 7.78(s, 1H), 8.14(t-like, J=6.9 Hz, 2H), 8.63(t, J=7.8 Hz, 1H), 8.92(s, 1H), 9.17(d, J=5.8 Hz, 2H), 10.12(s, 1H, NH)		30.0, 56.5, 59.7, 66.9, 104.4, 109.8, 115.9, 121.5(2C), 127.6, 128.4(2C), 129.4(2C), 130.3, 140.9, 141.2, 145.0, 145.5(2C), 145.8, 146.8, 149.5, 152.8
17	2.69(m, 2H), 3.68( s, 3H), 4.40(t, J=5.4 Hz, 2H), 4.97(t, J=6.6 Hz, 2H), 6.97(d, J=8.0 Hz, 2H), 7.17(s, 1H), 7.32(s, 1H),7.34(d, J=8.0 Hz, 2H), 8.14(t-like, J=6.6 Hz, 2H), 8.31(s, 1H), 8.65(t, J=7.7 Hz, 1H), 9.14(d, J=5.6 Hz, 2H)		29.8, 54.8, 59.7, 66.4, 101.2, 102.4, 118.6, 119.5(2C), 126.4, 128.0, 128.1(2C), 128.6(2C), 130.0, 131.1, 132.7, 140.5, 145.0(2C), 145.4, 150.1, 150.5

Compd.	IC₅₀/(μmol·L^-1)		Compd.	IC₅₀/(μmol·L^-1)
Compd.	AChE		BChE	AChE	BChE
6a	75.31±0.85	>150	6h	121.50±2.13	>150
6b	121.72±0.06	>150	6i	>150	>150
6c	111.22±2.39	>150	6j	109.68±1.67	>150
6d	94.14±0.52	>150	15	140.91±1.03	>150
6e	116.43±0.34	142.08±0.68	16	0.92±0.05	14.20±0.96
6f	120.29±1.43	>150	17	3.19±0.22	17.43±0.57
6g	136.23±1.45	>150	Galanthamine	2.30±0.03	20.47±1.92