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

doi:10.7503/cjcu20140223

Abstract

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

CLC Number:

O629

TrendMD:

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^†[J]. Chem. J. Chinese Universities, 2014, 35(11): 2353.

Figures/Tables 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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