马蹄金素杂环衍生物的合成及抗乙肝病毒活性

doi:10.7503/cjcu20140223

高等学校化学学报 ›› 2014, Vol. 35 ›› Issue (11): 2353.doi: 10.7503/cjcu20140223

马蹄金素杂环衍生物的合成及抗乙肝病毒活性

梁光平^1,², 胡占兴¹, 刘青川³, 黄正明³, 张建新¹, 梁光义¹(), 徐必学¹()

1. 贵州省中国科学院天然产物化学重点实验室, 贵阳 550002
2. 贵阳中医学院药学院, 贵阳 550002
3. 中国人民解放军第三〇二医院药学部, 北京 100039

收稿日期:2014-03-17 出版日期:2014-11-10 发布日期:2014-10-15
作者简介:联系人简介: 梁光义, 男, 教授, 博士生导师, 主要从事天然产物化学研究. E-mail:guangyi_liang@126.com ;徐必学, 男, 博士, 副研究员, 主要从事药物化学研究. E-mail:bixue_xu@126.com
基金资助:
国家自然科学基金(批准号: 81360472)和国家重大科学仪器设备开发专项(批准号: 2011YQ12003506)资助

Synthesis and Anti-hepatitis B Virus Activities of Heterocyclic Substituted Matijin-Su Derivatives^†

LIANG Guangping^1,², HU Zhanxing¹, LIU Qingchuan³, HUANG Zhengming³, ZHANG Jianxin¹, LIANG Guangyi^1,^*(), XU Bixue^1,^*()

1. Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academy of Sciences,Guiyang 550002, China
2. Department of Pharmacy, Guiyang College of Traditional Chinese Medicine, Guiyang 550002, China
3. Department of Pharmacy, No.302 Hospital of PLA, Beijing 100039, China

Received:2014-03-17 Online:2014-11-10 Published:2014-10-15
Contact: LIANG Guangyi,XU Bixue E-mail:guangyi_liang@126.com;bixue_xu@126.com
Supported by:
† Supported by the National Natural Science Foundation of China(No.81360472) and the National Significant Scientific Equipment Development Program, China(No.2011YQ12003506)

摘要/Abstract

摘要：

以马蹄金素[N-(N-苯甲酰基-L-苯丙氨酰基)-O-乙酰基-L-苯丙氨醇, MTS]为先导化合物, 设计并合成了16个杂环取代的马蹄金素衍生物, 其结构经NMR, ESI-MS和元素分析确证. 以HepG2 2.2.15细胞为乙肝病毒(HBV)载体, 对合成的马蹄金素衍生物进行了抗HBV活性测试. 实验结果表明, 在测试浓度范围内, 化合物5b(IC₅₀=8.20 μg/L, SI=10.26), 5g(IC₅₀=5.58 μg/L, SI=22.78)和5i(IC₅₀=5.07 μg/L, SI=16.67)的抗HBV活性较强; 在8 μg/mL的浓度下, 其抑制率分别为56.57%, 67.06%和66.83%.

关键词: 马蹄金素, 衍生物, 杂环, 抗乙肝病毒活性

Abstract:

N-(N-Benzoyl-L-phenylalanyl)-O-acetyl-L-phenylalanol was isolated from Dichondra repens Forst., which was a phenylalanine dipeptide compound with anti-HBV activity, named Matijin-Su(MTS). Its chemical skeleton structure was different from that of the existing drugs for anti-HBV. MTS was used as a lead compound base on the better anti-HBV activity by preliminary research. A series of MTS derivatives was designed and synthesized by a series of reactions, such as the formation of an amide(peptide), hydrolysis, condensation, acylation, alkylation and esterification using L-phenylalanine and its substitution as starting materials. The synthesized derivatives of MTS were characterized by ¹H NMR, ¹³C NMR, ESI MS and elemental analysis. Their anti-hepatitis B virus activities against HepG2 2.2.15 cells line in vitro were tested. From the screening results, compounds 5b(IC₅₀=8.20 μg/L, SI=10.26), 5g(IC₅₀=5.58 μg/L, SI=22.78) and 5i(IC₅₀=5.07 μg/L, SI=16.67) exhibited significant anti-HBV activities, the inhibition ratio were 56.57%, 67.06% and 66.83%, respectively.

Key words: Matijin-Su, Derivative, Heterocyclic, Anti-HBV activity

中图分类号:

O629

TrendMD:

梁光平, 胡占兴, 刘青川, 黄正明, 张建新, 梁光义, 徐必学. 马蹄金素杂环衍生物的合成及抗乙肝病毒活性. 高等学校化学学报, 2014, 35(11): 2353.

LIANG Guangping, HU Zhanxing, LIU Qingchuan, HUANG Zhengming, ZHANG Jianxin, LIANG Guangyi, XU Bixue. Synthesis and Anti-hepatitis B Virus Activities of Heterocyclic Substituted Matijin-Su Derivatives^†. Chem. J. Chinese Universities, 2014, 35(11): 2353.

图/表 5

Fig.1 Chemical structure of Matijin-Su(MTS)

Scheme 1 Synthetic routes of target compounds 4a—4g and 5a—5i

Table 1 Appearance, yields, melting points, optical rotation and elemental analysis for compounds 4a—4g and 5a—5i

Compd.	Appearance	Yield(%)^a	m. p. /℃	[α $] D 25$ /(°) (c=1, CHCl₃)	Elemental analysis(%, calcd. )
Compd.	Appearance	Yield(%)^a	m. p. /℃	[α $] D 25$ /(°) (c=1, CHCl₃)	C	H	N
4a	White solid	43.7	136—138	-8.7	67.62(67.59)	5.92(5.95)	6.86(6.80)
4b	White solid	43.6	152—155	+19.7	66.64(66.60)	5.82(5.85)	6.22(6.19)
4c	White solid	56.1	137—139	+26.4	63.70(63.69)	5.35(5.33)	6.19(6.21)
4d	White solid	48.8	182—185	-65.5^b	65.07(65.11)	5.70(5.68)	6.60(6.66)
4e	White solid	71.4	203—205	-68.8^b	67.63(67.65)	5.92(5.90)	6.86(6.85)
4f	White solid	68.2	158—160	+36.6	66.04(66.07)	5.54(5.49)	6.42(6.41)
4g	White solid	74.2	215—217	-25.9^b	67.10(67.06)	5.63(5.66)	9.39(9.42)
5a	White solid	57.1	138—140	-39.7	70.71(70.69)	7.37(7.40)	5.69(5.70)
5b	White solid	45.9	148—150	-33.6	68.47(68.50)	7.13(7.12)	5.51(5.52)
5c	White solid	51.2	142—145	-37.4	67.99(68.01)	6.93(6.92)	5.66(5.67)
5d	White solid	29.7	145—148	-45.8	65.73(65.71)	5.98(5.97)	6.39(6.41)
5e	White solid	35.4	140—143	+18.5	66.12(66.11)	6.34(6.36)	5.51(5.52)
5f	White solid	42.1	139—141	+17.2	64.36(64.33)	5.62(5.63)	6.00(6.04)
5g	White solid	58.2	153—156	+25.5	66.26(66.24)	6.55(6.57)	8.28(8.31)
5h	White solid	60.3	193—196	+43.1	67.16(67.13)	6.61(6.59)	10.80(10.82)
5i	White solid	39.1	177—178	+41.4	68.11(68.14)	7.01(6.99)	10.25(10.27)

Table 1 Appearance, yields, melting points, optical rotation and elemental analysis for compounds 4a—4g and 5a—5i

Compd.	Appearance	Yield(%)^a	m. p. /℃	[α $] D 25$ /(°) (c=1, CHCl₃)	Elemental analysis(%, calcd. )
Compd.	Appearance	Yield(%)^a	m. p. /℃	[α $] D 25$ /(°) (c=1, CHCl₃)	C	H	N
4a	White solid	43.7	136—138	-8.7	67.62(67.59)	5.92(5.95)	6.86(6.80)
4b	White solid	43.6	152—155	+19.7	66.64(66.60)	5.82(5.85)	6.22(6.19)
4c	White solid	56.1	137—139	+26.4	63.70(63.69)	5.35(5.33)	6.19(6.21)
4d	White solid	48.8	182—185	-65.5^b	65.07(65.11)	5.70(5.68)	6.60(6.66)
4e	White solid	71.4	203—205	-68.8^b	67.63(67.65)	5.92(5.90)	6.86(6.85)
4f	White solid	68.2	158—160	+36.6	66.04(66.07)	5.54(5.49)	6.42(6.41)
4g	White solid	74.2	215—217	-25.9^b	67.10(67.06)	5.63(5.66)	9.39(9.42)
5a	White solid	57.1	138—140	-39.7	70.71(70.69)	7.37(7.40)	5.69(5.70)
5b	White solid	45.9	148—150	-33.6	68.47(68.50)	7.13(7.12)	5.51(5.52)
5c	White solid	51.2	142—145	-37.4	67.99(68.01)	6.93(6.92)	5.66(5.67)
5d	White solid	29.7	145—148	-45.8	65.73(65.71)	5.98(5.97)	6.39(6.41)
5e	White solid	35.4	140—143	+18.5	66.12(66.11)	6.34(6.36)	5.51(5.52)
5f	White solid	42.1	139—141	+17.2	64.36(64.33)	5.62(5.63)	6.00(6.04)
5g	White solid	58.2	153—156	+25.5	66.26(66.24)	6.55(6.57)	8.28(8.31)
5h	White solid	60.3	193—196	+43.1	67.16(67.13)	6.61(6.59)	10.80(10.82)
5i	White solid	39.1	177—178	+41.4	68.11(68.14)	7.01(6.99)	10.25(10.27)

Table 2 1H NMR, 13C NMR and LC-MS data for compounds 4a—4g and 5a—5i

Compd.	¹H NMR(400 MHz, DMSO-d₆), δ	¹³C NMR(100 MHz, DMSO-d₆), δ	LC-MS, m/z
4a	8.46(1H, d, J=8.7 Hz, CONH), 8.03(1H, d, J=8.5 Hz, CONH), 7.81(1H, d, J=2.9 Hz, ThenoylH), 7.71(1H, d, J=4.2 Hz, ThenoylH), 7.25—7.20(8H, m, PhH), 7.16—7.10(3H, m, PhH, ThenoylH), 4.85(1H, t, J=5.3 Hz, OH), 4.61(1H, m, 2-H), 3.96(1H, m, 2'-H), 3.44(2H, m, 1'-H), 2.88(1H, m, 3a-H), 2.76—2.61(3H, m, 3b-H, 3'-H)	170.9, 160.8, 139.6, 139.1, 138.4, 130.9, 129.2, 129.1, 128.4, 128.0, 127.9, 126.2, 100.9, 62.9, 54.7, 52.5, 37.5, 36.7	409.1[M+H]⁺
4b	8.47(1H, d, J=7.5 Hz, CONH), 8.40(1H, d, J=8.6 Hz, CONH), 7.58(1H, d, J=3.3 Hz, ThenoylH), 7.30—7.14(10H, m, PhH), 6.80(1H, d, J=3.2 Hz, ThenoylH), 4.66(1H, m, 2-H), 4.49(1H, m, 2'-H), 3.57(3H, s, OCH₃), 3.05—2.97(3H, m, 3-H, 3'a-H), 2.89(1H, m, 3'b-H), 2.42(3H, s, CH₃)	171.8, 171.6, 160.9, 144.8, 138.2, 137.0, 136.8, 129.3, 129.1, 128.8, 128.3, 128.0, 126.6, 126.2, 54.2, 53.8, 51.9, 37.0, 36.6, 15.2	473.1[M+Na]⁺
4c	9.24(1H, s, OH), 8.61(1H, d, J=8.8 Hz, CONH), 8.49(1H, d, J=7.6 Hz, CONH), 7.82(1H, m, ThenoylH), 7.72(1H, m, ThenoylH), 7.35(2H, m, PhH), 7.29—7.23(4H, m, PhH, ThenoylH), 7.16(2H, m, PhH), 6.63(2H, m, PhH), 4.71(1H, m, 2-H), 4.47(1H, m, 2'-H), 3.58(3H, s, OCH₃), 3.07(1H, m, 3a-H), 2.98—2.85(3H, m, 3b-H, 3'-H)	171.9, 171.5, 161.0, 156.1, 139.4, 138.2, 131.0, 130.2, 130.0, 129.2, 128.6, 128.5, 128.1, 126.3, 115.1, 54.5, 53.7, 51.8, 37.3, 36.4	475.1[M+Na]⁺
4d	9.13(1H, s, OH), 8.47(1H, d, J=8.7 Hz, CONH), 7.84(1H, d, J=8.5 Hz, CONH), 7.81(1H, dd, J=1.1, 3.7 Hz, ThenoylH), 7.71(1H, dd, J=1.2, 5.0 Hz, ThenoylH), 7.22—7.13(6H, m, PhH, ThenoylH), 7.07(2H, m, PhH), 6.61(2H, m, PhH), 4.78(1H, t, J=5.5 Hz, OH), 4.54(1H, m, 2-H), 3.87(1H, m, 2'-H), 3.31(1H, m, 3a-H), 3.26(1H, m, 3b-H), 2.88(1H, m, 1'a-H), 2.83(1H, m, 1'b-H), 2.75(1H, m, 3'a-H), 2.63(1H, m, 3'b-H)	171.0, 160.9, 155.7, 139.7, 139.0, 130.9, 130.1, 129.2, 128.5, 128.3, 128.1, 127.9, 100.9, 114.9, 62.2, 55.0, 52.5, 36.6, 36.4	425.1[M+H]⁺
4e	9.15(1H, s, OH), 8.13(1H, d, J=8.8 Hz, CONH), 7.89(1H, d, J=8.4 Hz, CONH), 7.81(1H, d, J=5.6 Hz, FuroylH), 7.23—7.10(6H, m, PhH, FuroylH), 7.03(2H, d, J=8.4 Hz, PhH), 6.60(3H, m, PhH, FuroylH), 4.81(1H, t, J=6.4 Hz, OH), 4.56(1H, m, 2-H), 3.88(1H, m, 2'-H), 3.30(2H, m, 1'-H), 2.91—2.62(4H, m, 3-H, 3'-H)	170.7, 157.3, 155.7, 147.5, 145.1, 139.0, 130.1, 129.1, 128.1, 128.0, 125.9, 114.9, 113.7, 111.9, 62.3, 54.2, 52.5, 36.6	431.5[M+Na]⁺
4f	9.24(1H, s, OH), 8.49(1H, d, J=7.8 Hz, CONH), 8.32(1H, d, J=8.8 Hz, CONH), 7.80(1H, d, J=6.0 Hz, FuroylH), 7.29—7.10(6H, m, PhH, FuroylH), 7.00(2H, d, J=8.4 Hz, PhH), 6.62(2H, d, J=8.4 Hz, PhH), 6.58(1H, m, FuroylH), 4.72(1H, m, 2-H), 4.43(1H, m, 2'-H), 3.58(3H, s, OCH₃), 3.07—2.83(4H, m, 3-H, 3'-H)	172.0, 171.3, 157.5, 156.1, 147.4, 145.2, 138.0, 130.1, 129.2, 128.1, 127.0, 126.3, 115.1, 113.9, 111.9, 54.1, 53.7, 51.9, 37.0, 36.0	459.5[M+Na]⁺
4g	9.25(1H, s, PhH), 8.90(1H, d, J=8.8 Hz, CONH), 8.69(2H, d, J=5.2 Hz, IsonicotinoylH), 8.56(1H, d, J=7.6 Hz, CONH), 7.64(2H, d, J=5.2 Hz, IsonicotinoylH), 7.33(2H, d, J=7.6 Hz, PhH), 7.22(2H, m, PhH), 7.13(1H, m, PhH), 7.04(2H, d, J=8.0 Hz, PhH), 6.68(2H, d, J=8.0 Hz, PhH), 4.81(1H, m, 2-H), 4.40(1H, m, 2'-H), 3.61(3H, s, OCH₃), 3.11—2.87(4H, m, 3-H, 3'-H)	172.1, 171.1, 165.0, 156.2, 150.1, 141.0, 138.2, 130.2, 129.0, 128.1, 127.0, 126.2, 121.3, 114.9, 54.5, 54.0, 52.0, 36.9, 35.8	448.2[M+H]⁺
5a	8.15(1H, d, J=8.4 Hz, CONH), 7.89(1H, d, J=8.0 Hz, CONH), 7.81(1H, m, FuroylH), 7.18(3H, m, PhH, FuroylH), 7.13(5H, m, PhH), 6.75(2H, d, J=8.8 Hz, PhH), 6.59(1H, m, FuroylH), 4.81(1H, t, J=5.2 Hz, OH), 4.58(1H, m, 2-H), 3.90(1H, m, 2'-H), 3.86[2H, t, J=6.4 Hz, OCH₂(CH₂)₄CH₃],	170.6, 157.3, 157.2, 147.5, 145.0, 138.9, 130.1, 129.6, 129.1, 128.0, 100.8, 113.9, 113.7, 111.8, 67.2, 62.2, 54.1, 52.5, 36.5, 36.4,	493.2[M+H]⁺
Compd.	¹H NMR(400 MHz, DMSO-d₆), δ	¹³C NMR(100 MHz, DMSO-d₆), δ	LC-MS, m/z
5a	3.27(2H, m, 1'-H), 2.95—2.83(3H, m, 3-H, 3'a-H), 2.65(1H, m, 3'b-H), 1.64[2H, m, OCH₂CH₂(CH₂)₃CH₃], 1.36[2H, m, O(CH₂)₂CH₂(CH₂)₂CH₃], 1.26[4H, m, O(CH₂)₃(CH₂)₂CH₃], 0.84[3H, t, J=6.4 Hz, O(CH₂)₅CH₃]	31.0, 28.7, 25.2, 22.0, 13.8
5b	8.51(1H, d, J=8.6 Hz, CONH), 7.88(1H, d, J=8.4 Hz, CONH), 7.82(1H, dd, J=1.2, 3.8 Hz, ThenoylH), 7.72(1H, dd, J=1.2, 5.0 Hz, ThenoylH), 7.24—7.14(6H, m, PhH, ThenoylH), 7.11(2H, m, PhH), 6.77(2H, m, PhH), 4.78(2H, t, J=5.5 Hz, OCH₂(CH₂)₄CH₃), 4.56(1H, m, 2-H), 4.09(1H, m, 2'-H), 3.63(1H, d, J=6.6 Hz, OH), 3.32—3.22(2H, m, 1'-H), 2.92(1H, dd, J=4.5, 13.9 Hz, 3a-H), 2.86—2.78(3H, m, 3b-H, 3'-H), 1.65[2H, m, OCH₂CH₂(CH₂)₃CH₃], 1.35[2H, m, O(CH₂)₂CH₂(CH₂)₂CH₃], 1.26[4H, m, O(CH₂)₃(CH₂)₂·CH₃], 0.81[3H, t, J=6.4 Hz, O(CH₂)₅CH₃]	171.0, 160.9, 157.2, 139.7, 139.0, 131.0, 130.2, 130.0, 129.9, 129.2, 128.5, 128.1, 100.9, 114.0, 69.8, 67.2, 54.9, 52.4, 36.5, 31.1, 28.7, 25.3, 22.1, 14.0	531.2[M+Na]⁺
5c	8.52(1H, d, J=8.8 Hz, CONH), 7.88(1H, d, J=8.5 Hz, CONH), 7.82(1H, dd, J=1.0, 3.7 Hz, ThenoylH), 7.71(1H, dd, J=1.2, 5.0 Hz, ThenoylH), 7.24—7.09(8H, m, PhH, ThenoylH), 6.77(2H, m, PhH), 4.80(1H, d, J=6.8 Hz, OH), 4.56(1H, m, 2-H), 4.09(1H, m, 2'-H), 3.86[2H, m, OCH₂·(CH₂)₃CH₃], 3.34—3.24(2H, m, 1'-H), 2.93(1H, dd, J=4.5, 13.9 Hz, 3a-H), 2.86—2.81(3H, m, 3b-H, 3'-H), 1.64[2H, m, OCH₂CH₂(CH₂)₂CH₃], 1.33[4H, m, O(CH₂)₂(CH₂)₂CH₃], 0.87[3H, t, J=7.1 Hz, O(CH₂)₄CH₃]	171.0, 160.9, 157.2, 139.7, 139.0, 131.0, 130.2, 130.0, 129.9, 129.2, 128.5, 128.1, 100.9, 114.0, 69.8, 67.2, 54.9, 52.4, 36.5, 36.4, 28.5, 27.8, 21.9, 14.0	495.2[M+Na]⁺
5d	8.51(1H, d, J=8.4 Hz, CONH), 7.88(1H, d, J=8.4 Hz, CONH), 7.80(1H, d, J=2.8 Hz, ThenoylH), 7.71(1H, d, J=5.2 Hz, ThenoylH), 7.23—7.08(8H, m, PhH, ThenoylH), 6.77(2H, d, J=8.4 Hz, PhH), 4.87(1H, s, OH), 4.55(1H, m, 2-H), 3.87(1H, m, 2'-H), 3.65(3H, s, OCH₃), 3.30(2H, m, 1'-H), 2.93(1H, dd, J=4.4, 13.8 Hz, 3a-H), 2.83(2H, m, 3b-H, 3'a-H), 2.63(1H, dd, J=8.0, 13.6 Hz, 3'b-H)	171.1, 161.1, 157.9, 139.7, 139.1, 131.2, 130.4, 130.2, 129.4, 128.7, 128.2, 128.1, 126.1, 113.6, 62.4, 55.1, 52.9, 36.6	439.1[M+H]⁺
5e	8.54(1H, d, J=8.8 Hz, CONH), 8.42(1H, d, J=7.8 Hz, CONH), 7.77(1H, m, ThenoylH), 7.70(1H, m, ThenoylH), 7.33(2H, m, PhH), 7.29—7.21(4H, m, PhH, ThenoylH), 7.12(2H, m, PhH), 6.73(2H, m, PhH), 4.71(1H, m, 2-H), 4.47(1H, m, 2'-H), 3.89[2H, d, J=6.8 Hz, OCH₂(CH₂)₂CH₃], 3.58(3H, s, OCH₃), 3.07(1H, m, 3a-H), 2.98—2.85(3H, m, 3b-H, 3'-H), 1.68[4H, m, OCH₂(CH₂)₂CH₃], 0.90[3H, t, J=6.8 Hz, O(CH₂)₃CH₃]	171.9, 171.4, 160.9, 156.1, 139.2, 138.1, 131.0, 130.2, 130.0, 129.3, 128.6, 128.5, 128.0, 126.5, 114.2, 68.4, 54.5, 53.7, 52.1, 36.9, 35.9, 32.1, 19.2, 14.0	521.3[M+Na]⁺
5f	8.55(1H, d, J=8.8 Hz, CONH), 8.52(1H, d, J=7.5 Hz, CONH), 7.81(1H, dd, J=1.1, 3.8 Hz, ThenoylH), 7.71(1H, dd, J=1.2, 5.1 Hz, ThenoylH), 7.23—7.17(7H, m, PhH), 7.12(1H, dd, J=3.8, 5.1 Hz, ThenoylH), 6.79(2H, m, PhH), 4.64(1H, m, 2-H), 4.49(1H, m, 2'-H), 3.67(3H, s, OCH₃), 3.57(3H, s, OCH₃), 3.04(1H, dd, J=6.0, 13.8 Hz, 3a-H), 2.97(2H, m, 3b-H, 3'a-H), 2.84(1H, dd, J=11.0, 13.8 Hz, 3'b-H)	171.8, 171.7, 161.0, 157.8, 139.5, 137.0, 131.0, 130.2, 130.0, 129.1, 128.5, 128.3, 127.9, 126.6, 113.5, 54.9, 54.5, 53.8, 51.9, 36.6, 36.1	467.1[M+H]⁺
5g	8.49(1H, d, J=7.6 Hz, CONH), 8.30(1H, d, J=9.2 Hz, CONH), 7.79(1H, m, FuroylH), 7.27—7.20(4H, m, PhH), 7.16—7.09(4H, m, PhH, FuroylH), 6.76(2H, m, PhH), 6.58	171.9, 171.3, 157.5, 157.3, 147.4, 145.3, 138.0, 130.3, 129.2, 128.8, 128.2, 126.4,	508.1[M+H]⁺
Compd.	¹H NMR(400 MHz, DMSO-d₆), δ	¹³C NMR(100 MHz, DMSO-d₆), δ	LC-MS, m/z
5g	(1H, m, FuroylH), 4.70(1H, m, 2-H), 4.45(1H, m, 2'-H), 3.93[2H, m, OCH₂CH₂N(CH₃)₂], 3.58(3H, s, OCH₃), 3.05—3.85(4H, m, 3-H, 3'-H), 2.56[2H, t, J=5.6 Hz, OCH₂CH₂N·(CH₃)₂], 2.17[6H, s, OCH₂CH₂N(CH₃)₂]	114.3, 113.9, 111.9, 65.7, 57.7, 54.0, 53.7, 52.0, 45.6, 37.0, 35.9
5h	8.87(1H, d, J=8.8 Hz, CONH), 8.67(2H, m, IsonicotinoylH), 8.55(1H, d, J=7.6 Hz, CONH), 7.64(2H, m, IsonicotinoylH), 7.32(2H, m, PhH), 7.23(2H, m, PhH), 7.15(1H, m, PhH), 7.12(2H, m, PhH), 6.76(2H, m, PhH), 4.75(1H, m, 2-H), 4.44(1H, m, 2'-H), 3.91[2H, m, OCH₂CH₂N(CH₃)₂], 3.58(3H, s, OCH₃), 3.05(1H, dd, J=4.0, 11.6 Hz, 3a-H), 2.99—2.88(3H, m, 3b-H, 3'-H), 2.55[2H, t, J=5.6 Hz, OCH₂CH₂N·(CH₃)₂], 2.16[6H, s, OCH₂CH₂N(CH₃)₂]	171.9, 171.3, 164.7, 157.3, 150.2, 140.9, 138.1, 130.2, 129.2, 128.9, 128.1, 126.4, 121.4, 114.3, 65.7, 57.3, 54.5, 54.1, 52.0, 45.6, 37.0, 35.8	519.2[M+H]⁺
5i	8.87(1H, d, J=8.4 Hz, CONH), 8.66(2H, m, IsonicotinoylH), 8.56(1H, d, J=7.2 Hz, CONH), 7.63(2H, m, IsonicotinoylH), 7.30(2H, d, J=7.2 Hz, PhH), 7.22(2H, t, J=7.6 Hz, PhH), 7.13(1H, d, J=7.2 Hz, PhH), 7.09(2H, d, J=8.8 Hz, PhH), 6.74(2H, d, J=8.4 Hz, PhH), 4.75(1H, m, 2-H), 4.43(1H, m, 2'-H), 3.87[2H, m, OCH₂CH₂N(CH₂CH₃)₂], 3.56(3H, s, OCH₃), 3.05(1H, dd, J=4.0, 11.6 Hz, 3a-H), 2.91(3H, m, 3b-H, 3'-H), 2.70[2H, t, J=6.0 Hz, OCH₂CH₂N(CH₂CH₃)₂], 2.50[4H, m, OCH₂CH₂N(CH₂CH₃)₂], 0.92[6H, t, J=7.2 Hz, OCH₂CH₂N(CH₂CH₃)₂]	171.9, 171.3, 164.7, 157.3, 150.2, 140.9, 138.1, 130.2, 129.2, 128.9, 128.2, 126.4, 121.4, 114.3, 66.1, 54.6, 54.1, 52.0, 51.3, 47.0, 37.0, 35.8, 11.8	547.2[M+H]⁺

Table 2 1H NMR, 13C NMR and LC-MS data for compounds 4a—4g and 5a—5i

Compd.	¹H NMR(400 MHz, DMSO-d₆), δ	¹³C NMR(100 MHz, DMSO-d₆), δ	LC-MS, m/z
4a	8.46(1H, d, J=8.7 Hz, CONH), 8.03(1H, d, J=8.5 Hz, CONH), 7.81(1H, d, J=2.9 Hz, ThenoylH), 7.71(1H, d, J=4.2 Hz, ThenoylH), 7.25—7.20(8H, m, PhH), 7.16—7.10(3H, m, PhH, ThenoylH), 4.85(1H, t, J=5.3 Hz, OH), 4.61(1H, m, 2-H), 3.96(1H, m, 2'-H), 3.44(2H, m, 1'-H), 2.88(1H, m, 3a-H), 2.76—2.61(3H, m, 3b-H, 3'-H)	170.9, 160.8, 139.6, 139.1, 138.4, 130.9, 129.2, 129.1, 128.4, 128.0, 127.9, 126.2, 100.9, 62.9, 54.7, 52.5, 37.5, 36.7	409.1[M+H]⁺
4b	8.47(1H, d, J=7.5 Hz, CONH), 8.40(1H, d, J=8.6 Hz, CONH), 7.58(1H, d, J=3.3 Hz, ThenoylH), 7.30—7.14(10H, m, PhH), 6.80(1H, d, J=3.2 Hz, ThenoylH), 4.66(1H, m, 2-H), 4.49(1H, m, 2'-H), 3.57(3H, s, OCH₃), 3.05—2.97(3H, m, 3-H, 3'a-H), 2.89(1H, m, 3'b-H), 2.42(3H, s, CH₃)	171.8, 171.6, 160.9, 144.8, 138.2, 137.0, 136.8, 129.3, 129.1, 128.8, 128.3, 128.0, 126.6, 126.2, 54.2, 53.8, 51.9, 37.0, 36.6, 15.2	473.1[M+Na]⁺
4c	9.24(1H, s, OH), 8.61(1H, d, J=8.8 Hz, CONH), 8.49(1H, d, J=7.6 Hz, CONH), 7.82(1H, m, ThenoylH), 7.72(1H, m, ThenoylH), 7.35(2H, m, PhH), 7.29—7.23(4H, m, PhH, ThenoylH), 7.16(2H, m, PhH), 6.63(2H, m, PhH), 4.71(1H, m, 2-H), 4.47(1H, m, 2'-H), 3.58(3H, s, OCH₃), 3.07(1H, m, 3a-H), 2.98—2.85(3H, m, 3b-H, 3'-H)	171.9, 171.5, 161.0, 156.1, 139.4, 138.2, 131.0, 130.2, 130.0, 129.2, 128.6, 128.5, 128.1, 126.3, 115.1, 54.5, 53.7, 51.8, 37.3, 36.4	475.1[M+Na]⁺
4d	9.13(1H, s, OH), 8.47(1H, d, J=8.7 Hz, CONH), 7.84(1H, d, J=8.5 Hz, CONH), 7.81(1H, dd, J=1.1, 3.7 Hz, ThenoylH), 7.71(1H, dd, J=1.2, 5.0 Hz, ThenoylH), 7.22—7.13(6H, m, PhH, ThenoylH), 7.07(2H, m, PhH), 6.61(2H, m, PhH), 4.78(1H, t, J=5.5 Hz, OH), 4.54(1H, m, 2-H), 3.87(1H, m, 2'-H), 3.31(1H, m, 3a-H), 3.26(1H, m, 3b-H), 2.88(1H, m, 1'a-H), 2.83(1H, m, 1'b-H), 2.75(1H, m, 3'a-H), 2.63(1H, m, 3'b-H)	171.0, 160.9, 155.7, 139.7, 139.0, 130.9, 130.1, 129.2, 128.5, 128.3, 128.1, 127.9, 100.9, 114.9, 62.2, 55.0, 52.5, 36.6, 36.4	425.1[M+H]⁺
4e	9.15(1H, s, OH), 8.13(1H, d, J=8.8 Hz, CONH), 7.89(1H, d, J=8.4 Hz, CONH), 7.81(1H, d, J=5.6 Hz, FuroylH), 7.23—7.10(6H, m, PhH, FuroylH), 7.03(2H, d, J=8.4 Hz, PhH), 6.60(3H, m, PhH, FuroylH), 4.81(1H, t, J=6.4 Hz, OH), 4.56(1H, m, 2-H), 3.88(1H, m, 2'-H), 3.30(2H, m, 1'-H), 2.91—2.62(4H, m, 3-H, 3'-H)	170.7, 157.3, 155.7, 147.5, 145.1, 139.0, 130.1, 129.1, 128.1, 128.0, 125.9, 114.9, 113.7, 111.9, 62.3, 54.2, 52.5, 36.6	431.5[M+Na]⁺
4f	9.24(1H, s, OH), 8.49(1H, d, J=7.8 Hz, CONH), 8.32(1H, d, J=8.8 Hz, CONH), 7.80(1H, d, J=6.0 Hz, FuroylH), 7.29—7.10(6H, m, PhH, FuroylH), 7.00(2H, d, J=8.4 Hz, PhH), 6.62(2H, d, J=8.4 Hz, PhH), 6.58(1H, m, FuroylH), 4.72(1H, m, 2-H), 4.43(1H, m, 2'-H), 3.58(3H, s, OCH₃), 3.07—2.83(4H, m, 3-H, 3'-H)	172.0, 171.3, 157.5, 156.1, 147.4, 145.2, 138.0, 130.1, 129.2, 128.1, 127.0, 126.3, 115.1, 113.9, 111.9, 54.1, 53.7, 51.9, 37.0, 36.0	459.5[M+Na]⁺
4g	9.25(1H, s, PhH), 8.90(1H, d, J=8.8 Hz, CONH), 8.69(2H, d, J=5.2 Hz, IsonicotinoylH), 8.56(1H, d, J=7.6 Hz, CONH), 7.64(2H, d, J=5.2 Hz, IsonicotinoylH), 7.33(2H, d, J=7.6 Hz, PhH), 7.22(2H, m, PhH), 7.13(1H, m, PhH), 7.04(2H, d, J=8.0 Hz, PhH), 6.68(2H, d, J=8.0 Hz, PhH), 4.81(1H, m, 2-H), 4.40(1H, m, 2'-H), 3.61(3H, s, OCH₃), 3.11—2.87(4H, m, 3-H, 3'-H)	172.1, 171.1, 165.0, 156.2, 150.1, 141.0, 138.2, 130.2, 129.0, 128.1, 127.0, 126.2, 121.3, 114.9, 54.5, 54.0, 52.0, 36.9, 35.8	448.2[M+H]⁺
5a	8.15(1H, d, J=8.4 Hz, CONH), 7.89(1H, d, J=8.0 Hz, CONH), 7.81(1H, m, FuroylH), 7.18(3H, m, PhH, FuroylH), 7.13(5H, m, PhH), 6.75(2H, d, J=8.8 Hz, PhH), 6.59(1H, m, FuroylH), 4.81(1H, t, J=5.2 Hz, OH), 4.58(1H, m, 2-H), 3.90(1H, m, 2'-H), 3.86[2H, t, J=6.4 Hz, OCH₂(CH₂)₄CH₃],	170.6, 157.3, 157.2, 147.5, 145.0, 138.9, 130.1, 129.6, 129.1, 128.0, 100.8, 113.9, 113.7, 111.8, 67.2, 62.2, 54.1, 52.5, 36.5, 36.4,	493.2[M+H]⁺
Compd.	¹H NMR(400 MHz, DMSO-d₆), δ	¹³C NMR(100 MHz, DMSO-d₆), δ	LC-MS, m/z
5a	3.27(2H, m, 1'-H), 2.95—2.83(3H, m, 3-H, 3'a-H), 2.65(1H, m, 3'b-H), 1.64[2H, m, OCH₂CH₂(CH₂)₃CH₃], 1.36[2H, m, O(CH₂)₂CH₂(CH₂)₂CH₃], 1.26[4H, m, O(CH₂)₃(CH₂)₂CH₃], 0.84[3H, t, J=6.4 Hz, O(CH₂)₅CH₃]	31.0, 28.7, 25.2, 22.0, 13.8
5b	8.51(1H, d, J=8.6 Hz, CONH), 7.88(1H, d, J=8.4 Hz, CONH), 7.82(1H, dd, J=1.2, 3.8 Hz, ThenoylH), 7.72(1H, dd, J=1.2, 5.0 Hz, ThenoylH), 7.24—7.14(6H, m, PhH, ThenoylH), 7.11(2H, m, PhH), 6.77(2H, m, PhH), 4.78(2H, t, J=5.5 Hz, OCH₂(CH₂)₄CH₃), 4.56(1H, m, 2-H), 4.09(1H, m, 2'-H), 3.63(1H, d, J=6.6 Hz, OH), 3.32—3.22(2H, m, 1'-H), 2.92(1H, dd, J=4.5, 13.9 Hz, 3a-H), 2.86—2.78(3H, m, 3b-H, 3'-H), 1.65[2H, m, OCH₂CH₂(CH₂)₃CH₃], 1.35[2H, m, O(CH₂)₂CH₂(CH₂)₂CH₃], 1.26[4H, m, O(CH₂)₃(CH₂)₂·CH₃], 0.81[3H, t, J=6.4 Hz, O(CH₂)₅CH₃]	171.0, 160.9, 157.2, 139.7, 139.0, 131.0, 130.2, 130.0, 129.9, 129.2, 128.5, 128.1, 100.9, 114.0, 69.8, 67.2, 54.9, 52.4, 36.5, 31.1, 28.7, 25.3, 22.1, 14.0	531.2[M+Na]⁺
5c	8.52(1H, d, J=8.8 Hz, CONH), 7.88(1H, d, J=8.5 Hz, CONH), 7.82(1H, dd, J=1.0, 3.7 Hz, ThenoylH), 7.71(1H, dd, J=1.2, 5.0 Hz, ThenoylH), 7.24—7.09(8H, m, PhH, ThenoylH), 6.77(2H, m, PhH), 4.80(1H, d, J=6.8 Hz, OH), 4.56(1H, m, 2-H), 4.09(1H, m, 2'-H), 3.86[2H, m, OCH₂·(CH₂)₃CH₃], 3.34—3.24(2H, m, 1'-H), 2.93(1H, dd, J=4.5, 13.9 Hz, 3a-H), 2.86—2.81(3H, m, 3b-H, 3'-H), 1.64[2H, m, OCH₂CH₂(CH₂)₂CH₃], 1.33[4H, m, O(CH₂)₂(CH₂)₂CH₃], 0.87[3H, t, J=7.1 Hz, O(CH₂)₄CH₃]	171.0, 160.9, 157.2, 139.7, 139.0, 131.0, 130.2, 130.0, 129.9, 129.2, 128.5, 128.1, 100.9, 114.0, 69.8, 67.2, 54.9, 52.4, 36.5, 36.4, 28.5, 27.8, 21.9, 14.0	495.2[M+Na]⁺
5d	8.51(1H, d, J=8.4 Hz, CONH), 7.88(1H, d, J=8.4 Hz, CONH), 7.80(1H, d, J=2.8 Hz, ThenoylH), 7.71(1H, d, J=5.2 Hz, ThenoylH), 7.23—7.08(8H, m, PhH, ThenoylH), 6.77(2H, d, J=8.4 Hz, PhH), 4.87(1H, s, OH), 4.55(1H, m, 2-H), 3.87(1H, m, 2'-H), 3.65(3H, s, OCH₃), 3.30(2H, m, 1'-H), 2.93(1H, dd, J=4.4, 13.8 Hz, 3a-H), 2.83(2H, m, 3b-H, 3'a-H), 2.63(1H, dd, J=8.0, 13.6 Hz, 3'b-H)	171.1, 161.1, 157.9, 139.7, 139.1, 131.2, 130.4, 130.2, 129.4, 128.7, 128.2, 128.1, 126.1, 113.6, 62.4, 55.1, 52.9, 36.6	439.1[M+H]⁺
5e	8.54(1H, d, J=8.8 Hz, CONH), 8.42(1H, d, J=7.8 Hz, CONH), 7.77(1H, m, ThenoylH), 7.70(1H, m, ThenoylH), 7.33(2H, m, PhH), 7.29—7.21(4H, m, PhH, ThenoylH), 7.12(2H, m, PhH), 6.73(2H, m, PhH), 4.71(1H, m, 2-H), 4.47(1H, m, 2'-H), 3.89[2H, d, J=6.8 Hz, OCH₂(CH₂)₂CH₃], 3.58(3H, s, OCH₃), 3.07(1H, m, 3a-H), 2.98—2.85(3H, m, 3b-H, 3'-H), 1.68[4H, m, OCH₂(CH₂)₂CH₃], 0.90[3H, t, J=6.8 Hz, O(CH₂)₃CH₃]	171.9, 171.4, 160.9, 156.1, 139.2, 138.1, 131.0, 130.2, 130.0, 129.3, 128.6, 128.5, 128.0, 126.5, 114.2, 68.4, 54.5, 53.7, 52.1, 36.9, 35.9, 32.1, 19.2, 14.0	521.3[M+Na]⁺
5f	8.55(1H, d, J=8.8 Hz, CONH), 8.52(1H, d, J=7.5 Hz, CONH), 7.81(1H, dd, J=1.1, 3.8 Hz, ThenoylH), 7.71(1H, dd, J=1.2, 5.1 Hz, ThenoylH), 7.23—7.17(7H, m, PhH), 7.12(1H, dd, J=3.8, 5.1 Hz, ThenoylH), 6.79(2H, m, PhH), 4.64(1H, m, 2-H), 4.49(1H, m, 2'-H), 3.67(3H, s, OCH₃), 3.57(3H, s, OCH₃), 3.04(1H, dd, J=6.0, 13.8 Hz, 3a-H), 2.97(2H, m, 3b-H, 3'a-H), 2.84(1H, dd, J=11.0, 13.8 Hz, 3'b-H)	171.8, 171.7, 161.0, 157.8, 139.5, 137.0, 131.0, 130.2, 130.0, 129.1, 128.5, 128.3, 127.9, 126.6, 113.5, 54.9, 54.5, 53.8, 51.9, 36.6, 36.1	467.1[M+H]⁺
5g	8.49(1H, d, J=7.6 Hz, CONH), 8.30(1H, d, J=9.2 Hz, CONH), 7.79(1H, m, FuroylH), 7.27—7.20(4H, m, PhH), 7.16—7.09(4H, m, PhH, FuroylH), 6.76(2H, m, PhH), 6.58	171.9, 171.3, 157.5, 157.3, 147.4, 145.3, 138.0, 130.3, 129.2, 128.8, 128.2, 126.4,	508.1[M+H]⁺
Compd.	¹H NMR(400 MHz, DMSO-d₆), δ	¹³C NMR(100 MHz, DMSO-d₆), δ	LC-MS, m/z
5g	(1H, m, FuroylH), 4.70(1H, m, 2-H), 4.45(1H, m, 2'-H), 3.93[2H, m, OCH₂CH₂N(CH₃)₂], 3.58(3H, s, OCH₃), 3.05—3.85(4H, m, 3-H, 3'-H), 2.56[2H, t, J=5.6 Hz, OCH₂CH₂N·(CH₃)₂], 2.17[6H, s, OCH₂CH₂N(CH₃)₂]	114.3, 113.9, 111.9, 65.7, 57.7, 54.0, 53.7, 52.0, 45.6, 37.0, 35.9
5h	8.87(1H, d, J=8.8 Hz, CONH), 8.67(2H, m, IsonicotinoylH), 8.55(1H, d, J=7.6 Hz, CONH), 7.64(2H, m, IsonicotinoylH), 7.32(2H, m, PhH), 7.23(2H, m, PhH), 7.15(1H, m, PhH), 7.12(2H, m, PhH), 6.76(2H, m, PhH), 4.75(1H, m, 2-H), 4.44(1H, m, 2'-H), 3.91[2H, m, OCH₂CH₂N(CH₃)₂], 3.58(3H, s, OCH₃), 3.05(1H, dd, J=4.0, 11.6 Hz, 3a-H), 2.99—2.88(3H, m, 3b-H, 3'-H), 2.55[2H, t, J=5.6 Hz, OCH₂CH₂N·(CH₃)₂], 2.16[6H, s, OCH₂CH₂N(CH₃)₂]	171.9, 171.3, 164.7, 157.3, 150.2, 140.9, 138.1, 130.2, 129.2, 128.9, 128.1, 126.4, 121.4, 114.3, 65.7, 57.3, 54.5, 54.1, 52.0, 45.6, 37.0, 35.8	519.2[M+H]⁺
5i	8.87(1H, d, J=8.4 Hz, CONH), 8.66(2H, m, IsonicotinoylH), 8.56(1H, d, J=7.2 Hz, CONH), 7.63(2H, m, IsonicotinoylH), 7.30(2H, d, J=7.2 Hz, PhH), 7.22(2H, t, J=7.6 Hz, PhH), 7.13(1H, d, J=7.2 Hz, PhH), 7.09(2H, d, J=8.8 Hz, PhH), 6.74(2H, d, J=8.4 Hz, PhH), 4.75(1H, m, 2-H), 4.43(1H, m, 2'-H), 3.87[2H, m, OCH₂CH₂N(CH₂CH₃)₂], 3.56(3H, s, OCH₃), 3.05(1H, dd, J=4.0, 11.6 Hz, 3a-H), 2.91(3H, m, 3b-H, 3'-H), 2.70[2H, t, J=6.0 Hz, OCH₂CH₂N(CH₂CH₃)₂], 2.50[4H, m, OCH₂CH₂N(CH₂CH₃)₂], 0.92[6H, t, J=7.2 Hz, OCH₂CH₂N(CH₂CH₃)₂]	171.9, 171.3, 164.7, 157.3, 150.2, 140.9, 138.1, 130.2, 129.2, 128.9, 128.2, 126.4, 121.4, 114.3, 66.1, 54.6, 54.1, 52.0, 51.3, 47.0, 37.0, 35.8, 11.8	547.2[M+H]⁺

Table 3 Inhibition ratio for the replication of HBV DNA of compounds 4a—4g and 5a—5i

Compd.	Inhibition ratio(%)			TC₅₀/(μg·L^-1)	IC₅₀/(μg·L^-1)	SI
Compd.	20 μg/mL			TC₅₀/(μg·L^-1)	8 μg/mL	3.2 μg/mL
4a	38.85	40.61	36.26
4b	23.18	29.93	-2.14
4c	-16.62	16.53	12.52
4d	8.87	6.67	-3.43
4e	14.27	9.11	2.53
4f	-4.22	21.65	17.31
4g	15.83	29.06	-12.07
5a	25.03	41.09	38.09
5b	55.97	56.57	36.52	84.17	8.20	10.26
5c	26.47	28.37	0.81
5d	-18.46	10.79	6.29
5e	-72.36	7.06	-11.87
5f	-22.17	3.07	16.41
5g	66.73	67.06	47.75	127.11	5.58	22.78
5h	23.69	33.85	-9.49	55.72
5i	69.76	66.83	49.74	84.54	5.07	16.67
MTS				120.30	11.16	10.78
Lamivudine		97.74

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马蹄金素杂环衍生物的合成及抗乙肝病毒活性

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马蹄金素杂环衍生物的合成及抗乙肝病毒活性

Synthesis and Anti-hepatitis B Virus Activities of Heterocyclic Substituted Matijin-Su Derivatives†

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Synthesis and Anti-hepatitis B Virus Activities of Heterocyclic Substituted Matijin-Su Derivatives^†