2-甲氧/乙氧羰基-4-氟苯基-1,5-苯并硫氮杂䓬的合成、抑真菌活性及构效关系

doi:10.7503/cjcu20140353

摘要/Abstract

摘要：

以高活性的2-甲氧/乙氧羰基-4-(4-氟苯基)-1,5-苯并硫氮杂?A和B为模型化合物, 设计合成了11个含氟杂?衍生物3a~3k, 考察了它们对白色念珠菌和新生隐球菌的抑菌活性. 研究结果表明, 2-甲氧/乙氧羰基-4-(2-氟苯基)/(3-氟苯基)/(2,4-二氟苯基)-1,5-苯并硫氮杂?3a, 3b, 3d~3f对新生隐球菌有很强的抑菌活性, 3c的活性中等, 而7位氯代杂?3g~3k基本无活性; 上述杂?对白色念珠菌均无活性. 在此基础上, 进一步测试了高活性杂?3a, 3b, 3d~3f对新生隐球菌的抑菌浓度梯度、最小抑菌浓度(MIC)和最小杀菌浓度(MFC), 发现其MIC和MFC均远低于对照药氟康唑. 为了考察杂?3a~3f的药效基团, 又设计合成了4类杂?衍生物4a~4f, 5a~5f, 6a~6f和7a~7c, 通过对其抑菌活性的评价, 发现分子中2-甲氧/乙氧羰基和亚胺官能团对杂?3a~3f的抑真菌(新生隐球菌)活性起关键作用, 硫原子被氧原子或氮原子代替后原杂?的活性降低.

关键词: 1,5-苯并硫氮杂?, 抑菌活性, 构效关系

Abstract:

Using A and B as the prototypical structure, eleven 1,5-benzothiazepine derivatives 3a—3k were synthesized and evaluated for their antifungal activity against C. albicans and C. neoformans via the disk diffusion method. The results showed that benzothiazepines 3a, 3b and 3d—3f had good antifungal activity against C. neoformans, compound 3c had moderate activity, and 7-chloro-substituted analogues 3g—3k were weakly active or inactive. In addition, all of the benzothiazepines 3a—3k were almost inactive against C. albicans. Furthermore, compounds 3a, 3b and 3d—3f, which had good antifungal activities, were subjected to further pharmacological evaluation, including determining the dose dependence of the antifungal activity, minimum inhibitory concentration(MIC) and minimum fungicidal concentration(MFC) against C. neoformans. The results showed that the MIC and MFC values for above compounds were much lower than those of fluconazole. In order to examine the structural features responsible for the antifungal activity of compounds 3a—3f, four series of 1,5-benzothiazepine derivatives 4a—4f, 5a—5f, 6a—6f and 7a—7c were synthesized and screened for their antifungal activity. The results demonstrated that the methoxycarbonyl/ethoxycarbonyl group at the 2 position and imine moiety on the seven-membered ring of benzothiazepines 3a—3f was critical to their biological activity. The results also indicated that replacement of sulfur atom in the molecules with nitrogen or oxygen atom led to decrease in activity of this series of compounds.

Key words: 1,5-Benzothiazepine, Antifungal activity, Structure-activity relationship

中图分类号:

O626

TrendMD:

范世丽, 张博, 高丽叶, 王兰芝, 边艳青, 李媛. 2-甲氧/乙氧羰基-4-氟苯基-1,5-苯并硫氮杂䓬的合成、抑真菌活性及构效关系. 高等学校化学学报, 2014, 35(12): 2574.

FAN Shili, ZHANG Bo, GAO Liye, WANG Lanzhi, BIAN Yanqing, LI Yuan. Synthesis, Antifungal Activity and Structure-activity Relationship of 2-Methoxycarbonyl/ethoxycarbonyl-4-fluorophenyl-1,5-benzothiazepines^†. Chem. J. Chinese Universities, 2014, 35(12): 2574.

图/表 12

Fig.1 Structures of model compounds A, B and other designed compounds

Scheme 1 Synthetic routes of 1,5-benzothiazepines 3a—3k 3a—3c: R2=CH3, R1=o-F(3a), m-F(3b), 2,4-F2(3c); 3d—3f: R2=CH2CH3, R1=o-F(3d), m-F(3e), 2,4-F2(3f); 3g: R2=CH3, R1=p-F; 3h—3k: R2=CH2CH3, R1=p-F(3h), o-F(3i), m-F(3j), 2,4-F2(3k).

Table 1 Yields, melting points, HRMS and IR data for compounds 3a—3k

Compd.	Isolated yield(%)	m. p./℃	HRMS([M+H]⁺), m/z	IR(KBr), $ν ˙$ /cm^-1
3a	48.0	85—88	316.0806(316.0808)	1736.0, 1610.6
3b	72.5	102—104	316.0804(316.0808)	1728.3, 1614.5
3c	73.2	79—81	334.0712(334.0713)	1702.6, 1602.9
3d	70.1	58—60	330.0962(330.0964)	1716.7, 1601.0
3e	50.2	73—75	330.0958(330.0964)	1724.4, 1614.5
3f	53.2	71—73	348.0864(348.0870)	1716.7, 1604.8
3g	72.4	95—97	350.0412(350.0418)	1735.8, 1600.8
3h	75.8	104—106	364.0569(364.0574)	1718.6, 1599.0
3i	75.4	87—89	364.0569(364.0574)	1720.4, 1600.8
3j	77.1	107—108	364.0569(364.0574)	1720.6, 1618.3
3k	81.2	111—113	382.0745(382.0486)	1716.5, 1602.7

Table 1 Yields, melting points, HRMS and IR data for compounds 3a—3k

Compd.	Isolated yield(%)	m. p./℃	HRMS([M+H]⁺), m/z	IR(KBr), $ν ˙$ /cm^-1
3a	48.0	85—88	316.0806(316.0808)	1736.0, 1610.6
3b	72.5	102—104	316.0804(316.0808)	1728.3, 1614.5
3c	73.2	79—81	334.0712(334.0713)	1702.6, 1602.9
3d	70.1	58—60	330.0962(330.0964)	1716.7, 1601.0
3e	50.2	73—75	330.0958(330.0964)	1724.4, 1614.5
3f	53.2	71—73	348.0864(348.0870)	1716.7, 1604.8
3g	72.4	95—97	350.0412(350.0418)	1735.8, 1600.8
3h	75.8	104—106	364.0569(364.0574)	1718.6, 1599.0
3i	75.4	87—89	364.0569(364.0574)	1720.4, 1600.8
3j	77.1	107—108	364.0569(364.0574)	1720.6, 1618.3
3k	81.2	111—113	382.0745(382.0486)	1716.5, 1602.7

Table 2 1H NMR and 13C NMR data for compounds 3a—3k

Compd.	¹H NMR(500 MHz), δ	¹³C NMR(125 MHz), δ
3a^a	8.07—7.11(m, 8H, PhH), 4.52(dd, J=6.0, 11.5 Hz, 1H, SCH), 3.74(s, 3H, CH₃), 3.15(dd, J=11.5, 13.0 Hz, 1H, SCCH), 3.10(dd, J=6.0, 13.0 Hz, 1H, SCCH)	170.95,167.92(d, J=1.62 Hz), 162.38, 160.39, 151.62, 137.97, 135.49, 132.59(d, J=8.88 Hz), 131.43, 130.76(d, J=3.00 Hz), 130.66, 130.51, 126.90(d, J=11.50 Hz), 125.72, 124.95, 124.66(d, J=3.25 Hz), 124.53, 121.50, 118.29, 116.68, 116.40(d, J=10.38 Hz), 115.05, 55.45, 55.41, 52.62, 34.94, 34.90, 29.72
3b^a	7.80—7.08(m, 8H, PhH), 4.36(dd, J=6.0, 12.0 Hz, 1H, SCH), 3.77(s, 3H, CH₃), 3.17(dd, J=6.0, 13.5 Hz, 1H, SCCH), 3.13(dd, J=12.0, 13.5 Hz, 1H, SCCH)	170.73, 167.90(d, J=2.50 Hz), 164.13, 162.17, 152.30, 139.80(d, J=7.12 Hz), 135.50, 130.61, 130.34(d, J=7.88 Hz), 125.65, 125.01, 123.00(d, J=2.62 Hz), 120.93, 118.25(d, J=21.38 Hz), 114.21(d, J=22.88 Hz), 55.78, 52.75, 31.56
3c^a	8.13—6.88(m, 7H, PhH), 4.48(dd, J=6.0, 12.5 Hz, 1H, SCH), 3.75(s, 3H, CH₃), 3.13(dd, J=12.5, 13.0 Hz, 1H, SCCH), 3.07(dd, J=6.0, 13.0 Hz, 1H, SCCH)	170.88, 166.66, 164.65(dd, J=12.75, 252.88 Hz), 161.72(dd, J=12.00, 251.50 Hz), 151.51, 135.52, 132.24(dd, J=4.50, 9.75 Hz), 130.57, 125.79, 124.91, 123.24(dd, J=3.62, 11.12 Hz), 121.44, 112.28(dd, J=3.00, 20.88 Hz), 104.57(dd, J=25.62, 26.75 Hz), 55.41, 55.37, 52.67, 34.81, 34.76
3d^a	8.06—7.10(m, 8H, PhH), 4.48(dd, J=6.0, 12.0 Hz, 1H, SCH), 4.19(q, J=7.0 Hz, 2H, OCH₂), 3.15(dd, J=12.5, 12.5 Hz, 1H, SCCH), 3.10(dd, J=6.0, 13.0 Hz, 1H, SCCH), 1.28(t, J=7.0 Hz, 1H, CH₃)	170.41, 168.02, 162.36, 160.37, 151.74, 135.51, 132.49(d, J=8.62 Hz), 130.75(d, J=2.88 Hz), 130.44, 127.05(d, J=11.5 Hz), 125.62, 124.89, 124.63(d, J=3.38 Hz), 121.59, 116.37(d, J=23.00 Hz), 61.51, 55.75, 55.71, 34.93, 34.89, 14.08
3e^a	7.80—7.10(m, 8H, PhH), 4.33(dd, J=6.5, 11.5 Hz, 1H, SCH), 4.21(q, J=7.0 Hz, 2H, OCH₂), 3.16(dd, J=6.0, 13.0 Hz, 1H, SCCH), 3.12(dd, J=11.5, 13.0 Hz, 1H, SCCH), 1.30(t, J=7.0 Hz, 3H, CH₃)	170.15, 167.99(d, J=2.50 Hz), 164.13, 162.17, 152.37, 139.93(d, J=7.12 Hz), 135.51, 130.51, 130.28(d, J=7.75 Hz), 125.55, 124.94, 123.01, 121.11, 118.15(d, J=21.38 Hz), 114.21(d, J=22.75 Hz), 61.66, 56.11, 31.60, 14.08
3f^a	8.14—6.88(m, 7H, PhH), 4.45(dd, J=5.5, 12.0 Hz, 1H, SCH), 4.21—4.17(m, 2H, OCH₂), 3.14(dd, J=12.0, 13.0 Hz, 1H, SCCH), 3.07(dd, J=5.5, 13.0 Hz, 1H, SCCH), 1.28(t, J=7.0 Hz, 3H, CH₃)	170.30, 166.82, 164.63(dd, J=12.25, 252.50 Hz), 161.70(dd, J=12.12, 251.75 Hz), 151.56, 135.54, 132.24(dd, J=4.62, 9.88 Hz), 130.50, 125.71, 124.85, 123.34(dd, J=3.75, 11.25 Hz), 121.57, 112.23(dd, J=3.00, 21.00 Hz), 104.74, 104.53(dd, J=25.50, 26.88 Hz), 61.56, 55.72, 55.69, 34.81, 34.76, 14.08
3g^a	8.06—7.10(m, 7H, PhH), 4.34(dd, J=5.5, 12.5 Hz, 1H, SCH), 3.77(s, 3H, CH₃), 3.19(dd, J=5.5, 13.5 Hz, 1H, SCCH), 3.13(dd, J=12.5, 13.5 Hz, 1H, SCCH)	170.76, 167.87, 165.83, 163.83, 152.45, 136.37(d, J=17.88 Hz), 133.26(d, J=2.63 Hz), 130.57, 129.65(d, J=8.75 Hz), 125.14(d, J=66.12 Hz), 120.92, 115.93(d, J=21.62 Hz), 55.70, 52.70, 31.47
3h^a	8.05—7.08(m, 7H, PhH), 4.30(dd, J=5.5, 12.5 Hz, 1H, SCH), 4.21(q, J=7.0 Hz, 2H, OCH₂), 3.19(dd, J=5.5, 13.5 Hz, 1H, SCCH), 3.10(dd, J=12.5, 13.0 Hz, 1H, SCCH), 1.29(t, J=7.0 Hz, 3H, CH₃)	170.01, 168.96, 166.00, 163.99, 153.57, 136.39, 136.32, 133.73(d, J=8.75 Hz), 130.95(d, J=2.38 Hz), 129.63, 126.68(d, J=10.88 Hz), 125.24(d, J=3.00 Hz), 119.54, 117.06(d, J=22.50 Hz), 61.79, 55.85, 31.54, 14.09
3i^b	7.98—7.24(m, 7H, PhH), 4.62(dd, J=6.0, 12.0 Hz, 1H, SCH), 4.13—4.07(m, 2H, OCH₂), 3.16(dd, J=6.0, 13.5 Hz, 1H, SCCH), 2.94(dd, J=12.0, 13.0 Hz, 1H, SCCH), 2.50(t, J=2.0 Hz, 3H, CH₃)	170.00, 169.50, 162.19, 160.20, 153.17, 136.39, 136.32, 135.62, 133.32(d, J=2.62 Hz), 129.66(d, J=8.62 Hz), 126.72, 126.63, 125.10(d, J=66.12 Hz), 120.45, 117.15, 115.92(d, J=21.62 Hz), 61.63, 55.90, 55.87, 34.98, 34.94, 14.34
3j^a	7.79—7.08(m, 7H, PhH), 4.32(dd, J=5.5, 12.5 Hz, 1H, SCH), 4.21(q, J=7.0 Hz, 2H, OCH₂), 3.17(dd, J=6.0, 13.5 Hz, 1H, SCCH), 3.10(dd, J=12.5, 13.5 Hz, 1H, SCCH), 1.30(t, J=7.0 Hz, 3H, CH₃)	169.93, 169.09(d, J=2.62 Hz), 164.13, 162.17, 153.33, 139.43(d, J=7.12 Hz), 136.44, 136.35, 130.37(d, J=8.00 Hz), 125.59, 124.88, 123.09(d, J=2.75 Hz), 119.61, 118.56(d, J=21.12 Hz), 114.29(d, J=22.75 Hz), 61.81, 55.96, 31.69, 14.08
3k^a	8.13—6.89(m, 6H, PhH), 4.45(dd, J=7.0, 11.0 Hz, 1H, SCH), 4.22—4.16(m, 2H, OCH₂), 3.13(dd, J=11.0, 13.0 Hz, 1H, SCCH), 3.09(dd, J=6.5, 13.0 Hz, 1H, SCCH), 1.29(t, J=7.0 Hz, 3H, CH₃)	170.09, 167.85, 164.85(dd, J=12.62, 253.62 Hz), 161.84(dd, J=12.25, 251.88 Hz), 152.57, 136.39, 132.21(dd, J=4.38, 14.25 Hz), 125.72, 124.78, 122.91(dd, J=4.00, 11.25 Hz), 120.12, 112.36(dd, J=3.00, 21.00 Hz), 104.63(t, J=26.19 Hz), 104.42, 61.68, 55.55, 55.51, 34.92, 34.88, 14.08

Table 2 1H NMR and 13C NMR data for compounds 3a—3k

Compd.	¹H NMR(500 MHz), δ	¹³C NMR(125 MHz), δ
3a^a	8.07—7.11(m, 8H, PhH), 4.52(dd, J=6.0, 11.5 Hz, 1H, SCH), 3.74(s, 3H, CH₃), 3.15(dd, J=11.5, 13.0 Hz, 1H, SCCH), 3.10(dd, J=6.0, 13.0 Hz, 1H, SCCH)	170.95,167.92(d, J=1.62 Hz), 162.38, 160.39, 151.62, 137.97, 135.49, 132.59(d, J=8.88 Hz), 131.43, 130.76(d, J=3.00 Hz), 130.66, 130.51, 126.90(d, J=11.50 Hz), 125.72, 124.95, 124.66(d, J=3.25 Hz), 124.53, 121.50, 118.29, 116.68, 116.40(d, J=10.38 Hz), 115.05, 55.45, 55.41, 52.62, 34.94, 34.90, 29.72
3b^a	7.80—7.08(m, 8H, PhH), 4.36(dd, J=6.0, 12.0 Hz, 1H, SCH), 3.77(s, 3H, CH₃), 3.17(dd, J=6.0, 13.5 Hz, 1H, SCCH), 3.13(dd, J=12.0, 13.5 Hz, 1H, SCCH)	170.73, 167.90(d, J=2.50 Hz), 164.13, 162.17, 152.30, 139.80(d, J=7.12 Hz), 135.50, 130.61, 130.34(d, J=7.88 Hz), 125.65, 125.01, 123.00(d, J=2.62 Hz), 120.93, 118.25(d, J=21.38 Hz), 114.21(d, J=22.88 Hz), 55.78, 52.75, 31.56
3c^a	8.13—6.88(m, 7H, PhH), 4.48(dd, J=6.0, 12.5 Hz, 1H, SCH), 3.75(s, 3H, CH₃), 3.13(dd, J=12.5, 13.0 Hz, 1H, SCCH), 3.07(dd, J=6.0, 13.0 Hz, 1H, SCCH)	170.88, 166.66, 164.65(dd, J=12.75, 252.88 Hz), 161.72(dd, J=12.00, 251.50 Hz), 151.51, 135.52, 132.24(dd, J=4.50, 9.75 Hz), 130.57, 125.79, 124.91, 123.24(dd, J=3.62, 11.12 Hz), 121.44, 112.28(dd, J=3.00, 20.88 Hz), 104.57(dd, J=25.62, 26.75 Hz), 55.41, 55.37, 52.67, 34.81, 34.76
3d^a	8.06—7.10(m, 8H, PhH), 4.48(dd, J=6.0, 12.0 Hz, 1H, SCH), 4.19(q, J=7.0 Hz, 2H, OCH₂), 3.15(dd, J=12.5, 12.5 Hz, 1H, SCCH), 3.10(dd, J=6.0, 13.0 Hz, 1H, SCCH), 1.28(t, J=7.0 Hz, 1H, CH₃)	170.41, 168.02, 162.36, 160.37, 151.74, 135.51, 132.49(d, J=8.62 Hz), 130.75(d, J=2.88 Hz), 130.44, 127.05(d, J=11.5 Hz), 125.62, 124.89, 124.63(d, J=3.38 Hz), 121.59, 116.37(d, J=23.00 Hz), 61.51, 55.75, 55.71, 34.93, 34.89, 14.08
3e^a	7.80—7.10(m, 8H, PhH), 4.33(dd, J=6.5, 11.5 Hz, 1H, SCH), 4.21(q, J=7.0 Hz, 2H, OCH₂), 3.16(dd, J=6.0, 13.0 Hz, 1H, SCCH), 3.12(dd, J=11.5, 13.0 Hz, 1H, SCCH), 1.30(t, J=7.0 Hz, 3H, CH₃)	170.15, 167.99(d, J=2.50 Hz), 164.13, 162.17, 152.37, 139.93(d, J=7.12 Hz), 135.51, 130.51, 130.28(d, J=7.75 Hz), 125.55, 124.94, 123.01, 121.11, 118.15(d, J=21.38 Hz), 114.21(d, J=22.75 Hz), 61.66, 56.11, 31.60, 14.08
3f^a	8.14—6.88(m, 7H, PhH), 4.45(dd, J=5.5, 12.0 Hz, 1H, SCH), 4.21—4.17(m, 2H, OCH₂), 3.14(dd, J=12.0, 13.0 Hz, 1H, SCCH), 3.07(dd, J=5.5, 13.0 Hz, 1H, SCCH), 1.28(t, J=7.0 Hz, 3H, CH₃)	170.30, 166.82, 164.63(dd, J=12.25, 252.50 Hz), 161.70(dd, J=12.12, 251.75 Hz), 151.56, 135.54, 132.24(dd, J=4.62, 9.88 Hz), 130.50, 125.71, 124.85, 123.34(dd, J=3.75, 11.25 Hz), 121.57, 112.23(dd, J=3.00, 21.00 Hz), 104.74, 104.53(dd, J=25.50, 26.88 Hz), 61.56, 55.72, 55.69, 34.81, 34.76, 14.08
3g^a	8.06—7.10(m, 7H, PhH), 4.34(dd, J=5.5, 12.5 Hz, 1H, SCH), 3.77(s, 3H, CH₃), 3.19(dd, J=5.5, 13.5 Hz, 1H, SCCH), 3.13(dd, J=12.5, 13.5 Hz, 1H, SCCH)	170.76, 167.87, 165.83, 163.83, 152.45, 136.37(d, J=17.88 Hz), 133.26(d, J=2.63 Hz), 130.57, 129.65(d, J=8.75 Hz), 125.14(d, J=66.12 Hz), 120.92, 115.93(d, J=21.62 Hz), 55.70, 52.70, 31.47
3h^a	8.05—7.08(m, 7H, PhH), 4.30(dd, J=5.5, 12.5 Hz, 1H, SCH), 4.21(q, J=7.0 Hz, 2H, OCH₂), 3.19(dd, J=5.5, 13.5 Hz, 1H, SCCH), 3.10(dd, J=12.5, 13.0 Hz, 1H, SCCH), 1.29(t, J=7.0 Hz, 3H, CH₃)	170.01, 168.96, 166.00, 163.99, 153.57, 136.39, 136.32, 133.73(d, J=8.75 Hz), 130.95(d, J=2.38 Hz), 129.63, 126.68(d, J=10.88 Hz), 125.24(d, J=3.00 Hz), 119.54, 117.06(d, J=22.50 Hz), 61.79, 55.85, 31.54, 14.09
3i^b	7.98—7.24(m, 7H, PhH), 4.62(dd, J=6.0, 12.0 Hz, 1H, SCH), 4.13—4.07(m, 2H, OCH₂), 3.16(dd, J=6.0, 13.5 Hz, 1H, SCCH), 2.94(dd, J=12.0, 13.0 Hz, 1H, SCCH), 2.50(t, J=2.0 Hz, 3H, CH₃)	170.00, 169.50, 162.19, 160.20, 153.17, 136.39, 136.32, 135.62, 133.32(d, J=2.62 Hz), 129.66(d, J=8.62 Hz), 126.72, 126.63, 125.10(d, J=66.12 Hz), 120.45, 117.15, 115.92(d, J=21.62 Hz), 61.63, 55.90, 55.87, 34.98, 34.94, 14.34
3j^a	7.79—7.08(m, 7H, PhH), 4.32(dd, J=5.5, 12.5 Hz, 1H, SCH), 4.21(q, J=7.0 Hz, 2H, OCH₂), 3.17(dd, J=6.0, 13.5 Hz, 1H, SCCH), 3.10(dd, J=12.5, 13.5 Hz, 1H, SCCH), 1.30(t, J=7.0 Hz, 3H, CH₃)	169.93, 169.09(d, J=2.62 Hz), 164.13, 162.17, 153.33, 139.43(d, J=7.12 Hz), 136.44, 136.35, 130.37(d, J=8.00 Hz), 125.59, 124.88, 123.09(d, J=2.75 Hz), 119.61, 118.56(d, J=21.12 Hz), 114.29(d, J=22.75 Hz), 61.81, 55.96, 31.69, 14.08
3k^a	8.13—6.89(m, 6H, PhH), 4.45(dd, J=7.0, 11.0 Hz, 1H, SCH), 4.22—4.16(m, 2H, OCH₂), 3.13(dd, J=11.0, 13.0 Hz, 1H, SCCH), 3.09(dd, J=6.5, 13.0 Hz, 1H, SCCH), 1.29(t, J=7.0 Hz, 3H, CH₃)	170.09, 167.85, 164.85(dd, J=12.62, 253.62 Hz), 161.84(dd, J=12.25, 251.88 Hz), 152.57, 136.39, 132.21(dd, J=4.38, 14.25 Hz), 125.72, 124.78, 122.91(dd, J=4.00, 11.25 Hz), 120.12, 112.36(dd, J=3.00, 21.00 Hz), 104.63(t, J=26.19 Hz), 104.42, 61.68, 55.55, 55.51, 34.92, 34.88, 14.08

Scheme 2 Synthetic routes of compounds 4a—4f, 5a—5f and 6a—6f a—c. R2=CH3, R1=o-F(a), m-F(b), 2,4-F2(c); d—f. R2=C2H5, R1=o-F(d), m-F(e), 2,4-F2(f).

Scheme 3 Synthetic routes of compounds 7a—7c

Table 3 Yields, melting points, HRMS and IR data for compounds 4—7

Compd.	Isolated yield(%)	m. p./℃	HRMS([M+H]⁺), m/z	IR(KBr), $ν ˙$ /cm^-1
4a	34.1	73—74	300.1031(300.1030)	1732.1, 1610.6
4b	29.3	53—54	300.1031(300.1030)	1736.0, 1616.4
4c	32.0	57—58	318.0941(318.0936)	1734.0, 1610.6
4d	26.2	79—81	314.1190(314.1187)	1734.1, 1610.6
4e	31.5	27—29	314.1185(314.1187)	1730.2, 1616.4
4f	34.1	59—61	332.1096(332.1093)	1736.0, 1612.5
5a	49.1	71—73	299.1189(299.1190)	3365.9, 1734.1, 1604.8
5b	51.6	82—83	299.1192(299.1190)	3362.0, 1734.1, 1616.4
5c	50.0	128—130	317.1097(317.1096)	3362.0, 1739.8, 1610.6
5d	43.1	87—90	313.1350(313.1347)	3362.0, 1732.1, 1604.8
5e	41.3	97—99	313.1351(313.1347)	3375.5, 1734.1, 1608.7
5f	40.3	91—93	331.1256(331.1253)	3364.0, 1734.1, 1610.6
6a	49.5	79—81	318.0960(318.0958)	3392.9, 1720.6
6b	51.6	110—111	318.0960(318.0958)	3387.1, 1720.6
6c	56.3	96—97	336.0865(336.0864)	3311.9, 1739.8
6d	55.2	81—82	332.1112(332.1115)	3381.3, 1716.7
6e	52.7	53—54	332.1113(332.1115)	3375.5, 1728.3
6f	51.3	108—111	350.1024(350.1021)	3379.4, 1718.6
7a	55.4		258.0742(258.0747)	1608.7
7b	54.8		258.0742(258.0747)	1614.5
7c	57.4		276.0652(276.0653)	1610.6

Table 3 Yields, melting points, HRMS and IR data for compounds 4—7

Compd.	Isolated yield(%)	m. p./℃	HRMS([M+H]⁺), m/z	IR(KBr), $ν ˙$ /cm^-1
4a	34.1	73—74	300.1031(300.1030)	1732.1, 1610.6
4b	29.3	53—54	300.1031(300.1030)	1736.0, 1616.4
4c	32.0	57—58	318.0941(318.0936)	1734.0, 1610.6
4d	26.2	79—81	314.1190(314.1187)	1734.1, 1610.6
4e	31.5	27—29	314.1185(314.1187)	1730.2, 1616.4
4f	34.1	59—61	332.1096(332.1093)	1736.0, 1612.5
5a	49.1	71—73	299.1189(299.1190)	3365.9, 1734.1, 1604.8
5b	51.6	82—83	299.1192(299.1190)	3362.0, 1734.1, 1616.4
5c	50.0	128—130	317.1097(317.1096)	3362.0, 1739.8, 1610.6
5d	43.1	87—90	313.1350(313.1347)	3362.0, 1732.1, 1604.8
5e	41.3	97—99	313.1351(313.1347)	3375.5, 1734.1, 1608.7
5f	40.3	91—93	331.1256(331.1253)	3364.0, 1734.1, 1610.6
6a	49.5	79—81	318.0960(318.0958)	3392.9, 1720.6
6b	51.6	110—111	318.0960(318.0958)	3387.1, 1720.6
6c	56.3	96—97	336.0865(336.0864)	3311.9, 1739.8
6d	55.2	81—82	332.1112(332.1115)	3381.3, 1716.7
6e	52.7	53—54	332.1113(332.1115)	3375.5, 1728.3
6f	51.3	108—111	350.1024(350.1021)	3379.4, 1718.6
7a	55.4		258.0742(258.0747)	1608.7
7b	54.8		258.0742(258.0747)	1614.5
7c	57.4		276.0652(276.0653)	1610.6

Table 4 1H NMR and 13C NMR data for compounds 4—7

Compd.	¹H NMR(500 MHz), δ	¹³C NMR(125 MHz), δ
4a^a	8.07—6.94(m, 8H, PhH), 5.84(dd, J=3.0, 9.5 Hz, 1H, OCH), 3.69(s, 3H, OCH₃), 2.88(dd, J=9.5, 15.5 Hz, 1H, OCCH), 2.64(dd, J=1.5, 15.5 Hz, 1H, OCCH)	169.96, 162.17, 160.18, 157.65(d, J=2.88 Hz), 144.07, 133.03, 132.75(d, J=8.88 Hz), 130.53(d, J=2.88 Hz), 129.59, 127.78, 124.85(d, J=3.25 Hz), 123.61(d, J=11.75 Hz), 122.58, 116.83, 116.50(d, J=23.12 Hz), 70.05, 69.97, 52.06, 34.86
4b^a	7.81—6.94(m, 8H, PhH), 5.91(dd, J=2.5, 10.0 Hz, 1H, OCH), 3.73(s, 3H, OCH₃), 2.88(dd, J=5.5, 16.0 Hz, 1H, OCCH), 2.47(dd, J=3.0, 15.5 Hz, 1H, OCCH)	169.89, 164.18, 162.22, 157.66(d, J=2.75 Hz), 143.62, 136.87(d, J=7.25 Hz), 132.85, 130.49(d, J=8.12 Hz), 129.60, 127.88, 122.75, 122.31(d, J=2.88 Hz), 118.34(d, J=21.25 Hz), 116.88, 113.70(d, J=22.88 Hz), 68.02, 52.24, 35.30
4c^a	8.14—6.88(m, 7H, PhH), 5.80(dd, J=3.0, 10.0 Hz, 1H, OCH), 3.70(s, 3H, OCH₃), 2.87(dd, J=9.5, 16.0 Hz, 1H, OCCH), 2.61(dd, J=3.0, 16.0 Hz, 1H, OCCH)	169.87, 164.69(dd, J=12.25, 253.38 Hz), 161.51(dd, J=12.12, 252.38 Hz), 156.44, 156.41, 143.93, 132.92, 132.06(dd, J=4.62, 9.88 Hz), 129.65, 127.71, 122.65, 119.98(dd, J=3.88, 11.88 Hz), 116.87, 112.64(dd, J=3.38, 21.50 Hz), 104.68(t, J=26.12 Hz), 69.86, 69.78, 52.11, 34.78
4d^a	8.06—6.93(m, 8H, PhH), 5.84(dd, J=3.0, 10.0 Hz, 1H, OCH), 4.18—4.09(m, 2H, OCH₂), 2.85(dd, J=10.0, 15.5 Hz, 1H, OCCH), 2.62(dd, J=2.5, 15.5 Hz, 1H, OCCH), 1.23(t, J=7.0 Hz, 3H, CH₃)	169.52, 162.16, 160.16, 157.84(d, J=7.00 Hz), 144.15, 133.01, 132.74(d, J=8.88 Hz), 130.54(d, J=3.25 Hz), 129.57, 127.76, 124.88(d, J=3.12 Hz), 123.64(d, J=11.62 Hz), 122.54, 116.82, 116.51(d, J=23.12 Hz), 70.13, 70.05, 61.05, 35.13, 14.14
4e^a	7.84—6.96(m, 8H, PhH), 5.93(dd, J=3.5, 10.5 Hz, 1H, OCH), 4.21(m, 2H, OCH₂), 2.88(dd, J=10.0, 15.5 Hz, 1H), 2.48(dd, J=3.0, 16.0 Hz, 1H, OCCH), 1.29(t, J=7.0 Hz, 3H, CH₃)	169.41, 164.17, 162.21, 157.75(d, J=2.88 Hz), 143.74, 136.95(d, J=7.25 Hz), 132.91, 130.46(d, J=7.88 Hz), 129.54, 127.87, 122.68, 122.35(d, J=2.62 Hz), 118.36, 118.28(d, J=21.62 Hz), 116.85, 113.70(d, J=22.75 Hz), 68.10, 61.24, 35.61, 14.16
4f^a	8.14—6.88(m, 7H, PhH), 5.81(dd, J=3.0, 9.5 Hz, 1H, OCH), 4.15(m, 2H, OCH₂), 2.85(dd, J=10.0, 16.0 Hz, 1H, OCCH), 2.60(dd, J=1.5, 15.5 Hz, 1H, OCCH), 1.24(t, J=7.0 Hz, 3H, CH₃)	169.40, 164.67(dd, J=12.38, 253.50 Hz), 161.51(dd, J=12.25, 252.50 Hz), 156.59, 144.04, 132.95, 132.06(dd, J=5.00, 9.88 Hz), 129.61, 127.71, 122.59, 120.07(dd, J=4.00, 11.88 Hz), 116.84, 112.60(dd, J=3.25, 21.38 Hz), 104.67(t, J=26.25 Hz), 69.96, 69.88, 61.08, 35.11,
5a^a	7.97—7.00(m, 8H, PhH), 4.73(dd, J=4.0, 11.5 Hz, 1H, NCH), 4.38(s, 1H, NH), 3.78(s, 3H, OCH₃), 3.43(dd, J=4.0, 13.5 Hz, 1H, NCCH), 2.87(t, J=12.0 Hz, 1H, NCCH)	173.31, 164.85, 162.41, 160.43, 138.75, 137.57, 131.71(d, J=8.50 Hz), 130.52(d, J=3.25 Hz), 128.59, 128.36(d, J=12.12 Hz), 126.91, 124.53(d, J=3.00 Hz), 121.77(d, J=41.5 Hz), 116.16(d, J=22.62 Hz), 65.90, 65.87, 52.64, 35.13, 35.08
5b^b	7.80—6.84(m, 8H, PhH), 6.04(s, 1H, NCH), 4.70(m, 1H, NH), 3.53(s, 3H, OCH₃), 3.25(dd, J=8.0, 14.0 Hz, 1H, NCCH), 3.02(dd, J=4.0, 14.5 Hz, 1H, NCCH)	172.71, 163.76, 163.42, 161.83, 142.05(d, J=7.12 Hz), 139.74, 136.74, 130.86(d, J=8.12 Hz), 130.42, 127.24, 123.41, 120.83, 119.95, 117.23(d, J=21.12 Hz), 113.64(d, J=22.62 Hz), 64.31, 52.21, 33.28
5c^a	8.00—6.90(m, 7H, PhH), 4.70(dd, J=4.0, 11.5 Hz, 1H, NCH), 4.36(s, 1H, NH), 3.79(s, 3H, OCH₃), 3.40(dd, J=3.0, 13.5 Hz, 1H, NCCH), 2.85(t, J=13.0 Hz, 1H, NCCH)	173.15, 164.09(dd, J=12.12, 263.12 Hz), 161.64(dd, J=11.75, 250.25 Hz), 138.60, 137.51, 131.88(dd, J=5.12, 9.75 Hz), 128.57, 126.98, 124.68(dd, J=3.62, 12.00 Hz), 122.00, 121.60, 112.00(dd, J=3.12, 21.38 Hz), 104.34(t, J=25.88 Hz), 65.83, 52.65, 35.03, 34.98
5d^a	7.94—6.98(m, 8H, PhH), 4.68(dd, J=4.0, 11.5 Hz, 1H, NCH), 4.30(s, 1H, NH), 4.23—4.19(m, 2H, OCH₂), 3.41(dd, J=4.0, 13.5 Hz, 1H, NCCH), 2.85(dd, J=11.5, 13.5 Hz, 1H, NCCH), 1.27(t, J=7.0 Hz, 3H, CH₃)	172.81, 165.02, 162.40, 160.42, 138.72, 137.67, 131.71(d, J=8.50 Hz), 130.54(d, J=3.25 Hz), 128.60, 128.41(d, J=12.00 Hz), 126.91, 124.54(d, J=3.00 Hz), 121.74(d, J=33.62 Hz), 116.17(d, J=22.38 Hz), 66.02, 61.79, 35.17, 35.12, 14.19
5e^a	7.79—6.96(m, 8H, PhH), 4.53(dd, J=4.0, 11.0 Hz, 1H, NCH), 4.34(s, 1H, NH), 4.24(q, J=7.0 Hz, 2H, OCH₂), 3.45(dd, J=4.0, 13.5 Hz, 1H, NCCH), 2.86(dd, J=11.0, 13.5 Hz, 1H, NCCH), 1.31(t, J=7.0 Hz, 3H, CH₃)	172.47, 164.49(d, J=2.38 Hz), 164.11, 162.16, 141.14, 141.06(d, J=7.00 Hz), 138.95, 137.38, 130.14, 130.05(d, J=8.00 Hz), 128.85, 126.94, 122.70(d, J=2.62 Hz), 122.06, 121.47, 117.35(d, J=21.38 Hz), 114.10, 113.95(d, J=22.62 Hz), 66.12, 62.04, 32.03, 14.29
5f^a	7.99—6.87(m, 7H, PhH), 4.65(dd, J=4.0, 11.5 Hz, 1H, NCH), 4.36(s, 1H, NH), 4.23—4.19(m, 2H, OCH₂), 3.37(dd, J=4.0, 13.5 Hz, 1H, NCCH), 2.83(dd, J=11.5, 13.5 Hz, 1H, NCCH), 1.28(t, J=7.5 Hz, 3H, CH₃)	172.67, 164.08(dd, J=12.12, 251.25 Hz), 161.64(dd, J=12.25, 250.88 Hz), 138.55, 137.61, 131.90(dd, J=4.88, 9.75 Hz), 128.57, 127.00, 124.71(dd, J=3.75, 11.88 Hz), 121.95, 121.61, 112.01(dd, J=3.25, 21.25 Hz), 104.35(t, J=26.00 Hz), 65.95, 61.83, 35.06, 35.01, 14.19
6a^b	7.78—6.70(m, 8H, PhH), 5.46(d, J=3.0 Hz, 1H, NH), 5.27—5.25(m, 1H, NCH), 4.11(dd, J=4.5, 9.5 Hz, 1H,SCH ), 3.62(s, 3H,OCH₃ ), 2.51—2.46(m, 1H, SCCH), 2.23—2.17(m, 1H, SCCH)	171.52, 160.85, 158.90, 150.15, 132.94, 129.95(d, J=13.38 Hz), 129.78(d, J=8.25 Hz), 129.65(d, J=3.75 Hz), 128.97, 125.01(d, J=2.88 Hz), 120.44(d, J=20.5 Hz), 119.20, 115.89(d, J=21.88 Hz), 52.79, 50.49, 43.80, 37.55
6b^c	7.45—6.77(m, 8H, PhH), 5.13—5.10(m, 1H, NCH), 4.85(s, 1H, NH), 4.07(dd, J=4.5, 9.5 Hz, 1H, SCH), 3.67(s, 3H, OCH₃), 2.50—2.45(m, 1H, SCCH), 2.41—2.36(m, 1H, SCCH)	171.24, 163.87, 161.93, 149.58, 146.41(d, J=7.00 Hz), 132.86, 130.41(d, J=8.12 Hz), 128.69, 123.03(d, J=2.75 Hz), 120.64, 120.01, 119.89, 114.14(d, J=18.12 Hz), 113.97(d, J=19.00 Hz), 56.98, 51.74, 43.12, 38.68
6c^c	7.94—6.78(m, 7H, PhH), 5.40—5.38(m, 1H, NCH), 4.87(s, 1H, NH), 4.08(t, J=10.0 Hz, 1H, SCH), 3.67(s, 3H, OCH₃), 2.57—2.52(m, 1H, SCCH), 2.36—2.31(m, 1H, SCCH)	171.16, 162.24(dd, J=12.12, 245.00 Hz), 160.02(dd, J=12.12, 246.62 Hz), 149.54, 132.82, 130.43(dd, J=6.00, 9.75 Hz), 128.70, 126.27(dd, J=3.62, 13.88 Hz), 120.73, 119.98, 119.87, 111.26(dd, J=3.38, 21.00 Hz), 103.60(t, J=26.00 Hz), 51.73, 50.26, 43.19, 36.93
6d^c	7.86—6.79(m, 8H, PhH), 5.48—5.47(m, 1H, NCH), 4.81(s, 1H, NH), 4.16—4.13(m, 3H, OCH₂, SCH), 2.60—2.54(m, 1H, SCCH), 2.39—2.34(m, 1H, SCCH), 1.23(t, J=7.0 Hz, 3H, CH₃)	170.60, 160.85, 158.90, 149.66, 132.72, 129.96(d, J=13.50 Hz), 129.30(d, J=8.62 Hz), 129.02(d, J=4.25 Hz), 128.53, 124.54(d, J=3.50 Hz), 120.60, 120.04, 119.98, 115.39(d, J=22.00 Hz), 60.89, 50.70, 43.81, 37.55, 13.55
6e^c	7.46—6.78(m, 8H, PhH), 5.12—5.10(m, 1H, NCH), 4.84(s, 1H, NH), 4.17—4.07(m, 2H, OCH₂), 4.04(dd, J=4.5, 10.0 Hz, 1H, SCH), 2.50—2.44(m, 1H, SCCH), 2.41—2.36(m, 1H, SCCH), 1.21(t, J=7.0 Hz, 3H, CH₃)	170.67, 163.87, 161.93, 149.66, 146.50(d, J=7.00 Hz), 132.92, 130.40(d, J=8.25 Hz), 128.65, 123,02(d, J=2.62 Hz), 120.62, 120.02, 114.11(d, J=17.25 Hz), 113.94(d, J=18.12 Hz), 60.84, 57.01, 43.28, 38.74, 13.53
6f^b	7.84—6.71(m, 7H, PhH), 5.48(d, J=3.0 Hz, 1H, NH), 5.18(d, J=9.0 Hz, 1H, NCH), 4.01—4.04(m, 2H, OCH₂), 4.02(dd, J=4.5, 9.5 Hz, 1H, SCH), 2.45(dd, J=9.0, 9.5 Hz, 1H, SCCH), 2.21—2.15(m, 1H, SCCH)	170.96, 162.04(dd, J=12.75, 244.38 Hz), 159.96(dd, J=12.62, 246.50 Hz), 133.13, 130.96(dd, J=6.00, 9.75 Hz), 129.06, 126.46(dd, J=3.38, 13.62 Hz), 120.62, 120.37, 119.31, 111.89(dd, J=3.00, 20.75 Hz), 104.35(t, J=25.88 Hz), 61.42, 50.10, 43.68, 37.23, 14.40
7a^a	8.07—7.08(m, 8H, PhH), 3.68(t, J=6.75 Hz, 2H, SCH₂), 2.94(t, J=6.75 Hz, 2H, SCCH₂)	169.73, 162.35, 160.36, 152.18, 134.77, 132.22(d, J=8.88 Hz), 130.79(d, J=3.25 Hz), 129.56, 127.32(d, J=11.62 Hz), 125.16(d, J=25.25 Hz), 124.54(d, J=3.25 Hz), 116.32(d, J=22.88 Hz), 41.19, 30.60
7b^a	7.72—7.00(m, 8H, PhH), 3.57(t, J=7.0 Hz, 2H, SCH₂), 2.88(t, J=7.0 Hz, 2H, SCCH₂)	169.71, 164.13, 162.17,152.75, 140.23(d, J=7.12 Hz), 134.83, 130.21(d, J=8.00 Hz), 129.66, 125.16(d, J=14.38 Hz), 123.35, 122.93(d, J=2.62 Hz), 117.89(d, J=21.50 Hz), 114.15(d, J=22.62 Hz), 41.65, 29.74
7c^a	8.13—6.88(m, 7H, PhH), 3.67(t, J=6.75 Hz, 2H, SCH₂), 2.91(t, J=6.75 Hz, 2H, SCCH₂)	168.49, 164.47(dd, J=12.25, 251.88 Hz), 161.68(dd, J=12.25, 251.75 Hz), 152.00, 134.79, 132.22(dd, J=4.75, 77.00 Hz), 129.62, 125.34, 125.01, 123.59(dd, J=3.62, 11.62 Hz), 112.08(dd, J=3.12, 21.00 Hz), 104.46(t, J=26.12 Hz), 41.17, 32.91

Table 4 1H NMR and 13C NMR data for compounds 4—7

Compd.	¹H NMR(500 MHz), δ	¹³C NMR(125 MHz), δ
4a^a	8.07—6.94(m, 8H, PhH), 5.84(dd, J=3.0, 9.5 Hz, 1H, OCH), 3.69(s, 3H, OCH₃), 2.88(dd, J=9.5, 15.5 Hz, 1H, OCCH), 2.64(dd, J=1.5, 15.5 Hz, 1H, OCCH)	169.96, 162.17, 160.18, 157.65(d, J=2.88 Hz), 144.07, 133.03, 132.75(d, J=8.88 Hz), 130.53(d, J=2.88 Hz), 129.59, 127.78, 124.85(d, J=3.25 Hz), 123.61(d, J=11.75 Hz), 122.58, 116.83, 116.50(d, J=23.12 Hz), 70.05, 69.97, 52.06, 34.86
4b^a	7.81—6.94(m, 8H, PhH), 5.91(dd, J=2.5, 10.0 Hz, 1H, OCH), 3.73(s, 3H, OCH₃), 2.88(dd, J=5.5, 16.0 Hz, 1H, OCCH), 2.47(dd, J=3.0, 15.5 Hz, 1H, OCCH)	169.89, 164.18, 162.22, 157.66(d, J=2.75 Hz), 143.62, 136.87(d, J=7.25 Hz), 132.85, 130.49(d, J=8.12 Hz), 129.60, 127.88, 122.75, 122.31(d, J=2.88 Hz), 118.34(d, J=21.25 Hz), 116.88, 113.70(d, J=22.88 Hz), 68.02, 52.24, 35.30
4c^a	8.14—6.88(m, 7H, PhH), 5.80(dd, J=3.0, 10.0 Hz, 1H, OCH), 3.70(s, 3H, OCH₃), 2.87(dd, J=9.5, 16.0 Hz, 1H, OCCH), 2.61(dd, J=3.0, 16.0 Hz, 1H, OCCH)	169.87, 164.69(dd, J=12.25, 253.38 Hz), 161.51(dd, J=12.12, 252.38 Hz), 156.44, 156.41, 143.93, 132.92, 132.06(dd, J=4.62, 9.88 Hz), 129.65, 127.71, 122.65, 119.98(dd, J=3.88, 11.88 Hz), 116.87, 112.64(dd, J=3.38, 21.50 Hz), 104.68(t, J=26.12 Hz), 69.86, 69.78, 52.11, 34.78
4d^a	8.06—6.93(m, 8H, PhH), 5.84(dd, J=3.0, 10.0 Hz, 1H, OCH), 4.18—4.09(m, 2H, OCH₂), 2.85(dd, J=10.0, 15.5 Hz, 1H, OCCH), 2.62(dd, J=2.5, 15.5 Hz, 1H, OCCH), 1.23(t, J=7.0 Hz, 3H, CH₃)	169.52, 162.16, 160.16, 157.84(d, J=7.00 Hz), 144.15, 133.01, 132.74(d, J=8.88 Hz), 130.54(d, J=3.25 Hz), 129.57, 127.76, 124.88(d, J=3.12 Hz), 123.64(d, J=11.62 Hz), 122.54, 116.82, 116.51(d, J=23.12 Hz), 70.13, 70.05, 61.05, 35.13, 14.14
4e^a	7.84—6.96(m, 8H, PhH), 5.93(dd, J=3.5, 10.5 Hz, 1H, OCH), 4.21(m, 2H, OCH₂), 2.88(dd, J=10.0, 15.5 Hz, 1H), 2.48(dd, J=3.0, 16.0 Hz, 1H, OCCH), 1.29(t, J=7.0 Hz, 3H, CH₃)	169.41, 164.17, 162.21, 157.75(d, J=2.88 Hz), 143.74, 136.95(d, J=7.25 Hz), 132.91, 130.46(d, J=7.88 Hz), 129.54, 127.87, 122.68, 122.35(d, J=2.62 Hz), 118.36, 118.28(d, J=21.62 Hz), 116.85, 113.70(d, J=22.75 Hz), 68.10, 61.24, 35.61, 14.16
4f^a	8.14—6.88(m, 7H, PhH), 5.81(dd, J=3.0, 9.5 Hz, 1H, OCH), 4.15(m, 2H, OCH₂), 2.85(dd, J=10.0, 16.0 Hz, 1H, OCCH), 2.60(dd, J=1.5, 15.5 Hz, 1H, OCCH), 1.24(t, J=7.0 Hz, 3H, CH₃)	169.40, 164.67(dd, J=12.38, 253.50 Hz), 161.51(dd, J=12.25, 252.50 Hz), 156.59, 144.04, 132.95, 132.06(dd, J=5.00, 9.88 Hz), 129.61, 127.71, 122.59, 120.07(dd, J=4.00, 11.88 Hz), 116.84, 112.60(dd, J=3.25, 21.38 Hz), 104.67(t, J=26.25 Hz), 69.96, 69.88, 61.08, 35.11,
5a^a	7.97—7.00(m, 8H, PhH), 4.73(dd, J=4.0, 11.5 Hz, 1H, NCH), 4.38(s, 1H, NH), 3.78(s, 3H, OCH₃), 3.43(dd, J=4.0, 13.5 Hz, 1H, NCCH), 2.87(t, J=12.0 Hz, 1H, NCCH)	173.31, 164.85, 162.41, 160.43, 138.75, 137.57, 131.71(d, J=8.50 Hz), 130.52(d, J=3.25 Hz), 128.59, 128.36(d, J=12.12 Hz), 126.91, 124.53(d, J=3.00 Hz), 121.77(d, J=41.5 Hz), 116.16(d, J=22.62 Hz), 65.90, 65.87, 52.64, 35.13, 35.08
5b^b	7.80—6.84(m, 8H, PhH), 6.04(s, 1H, NCH), 4.70(m, 1H, NH), 3.53(s, 3H, OCH₃), 3.25(dd, J=8.0, 14.0 Hz, 1H, NCCH), 3.02(dd, J=4.0, 14.5 Hz, 1H, NCCH)	172.71, 163.76, 163.42, 161.83, 142.05(d, J=7.12 Hz), 139.74, 136.74, 130.86(d, J=8.12 Hz), 130.42, 127.24, 123.41, 120.83, 119.95, 117.23(d, J=21.12 Hz), 113.64(d, J=22.62 Hz), 64.31, 52.21, 33.28
5c^a	8.00—6.90(m, 7H, PhH), 4.70(dd, J=4.0, 11.5 Hz, 1H, NCH), 4.36(s, 1H, NH), 3.79(s, 3H, OCH₃), 3.40(dd, J=3.0, 13.5 Hz, 1H, NCCH), 2.85(t, J=13.0 Hz, 1H, NCCH)	173.15, 164.09(dd, J=12.12, 263.12 Hz), 161.64(dd, J=11.75, 250.25 Hz), 138.60, 137.51, 131.88(dd, J=5.12, 9.75 Hz), 128.57, 126.98, 124.68(dd, J=3.62, 12.00 Hz), 122.00, 121.60, 112.00(dd, J=3.12, 21.38 Hz), 104.34(t, J=25.88 Hz), 65.83, 52.65, 35.03, 34.98
5d^a	7.94—6.98(m, 8H, PhH), 4.68(dd, J=4.0, 11.5 Hz, 1H, NCH), 4.30(s, 1H, NH), 4.23—4.19(m, 2H, OCH₂), 3.41(dd, J=4.0, 13.5 Hz, 1H, NCCH), 2.85(dd, J=11.5, 13.5 Hz, 1H, NCCH), 1.27(t, J=7.0 Hz, 3H, CH₃)	172.81, 165.02, 162.40, 160.42, 138.72, 137.67, 131.71(d, J=8.50 Hz), 130.54(d, J=3.25 Hz), 128.60, 128.41(d, J=12.00 Hz), 126.91, 124.54(d, J=3.00 Hz), 121.74(d, J=33.62 Hz), 116.17(d, J=22.38 Hz), 66.02, 61.79, 35.17, 35.12, 14.19
5e^a	7.79—6.96(m, 8H, PhH), 4.53(dd, J=4.0, 11.0 Hz, 1H, NCH), 4.34(s, 1H, NH), 4.24(q, J=7.0 Hz, 2H, OCH₂), 3.45(dd, J=4.0, 13.5 Hz, 1H, NCCH), 2.86(dd, J=11.0, 13.5 Hz, 1H, NCCH), 1.31(t, J=7.0 Hz, 3H, CH₃)	172.47, 164.49(d, J=2.38 Hz), 164.11, 162.16, 141.14, 141.06(d, J=7.00 Hz), 138.95, 137.38, 130.14, 130.05(d, J=8.00 Hz), 128.85, 126.94, 122.70(d, J=2.62 Hz), 122.06, 121.47, 117.35(d, J=21.38 Hz), 114.10, 113.95(d, J=22.62 Hz), 66.12, 62.04, 32.03, 14.29
5f^a	7.99—6.87(m, 7H, PhH), 4.65(dd, J=4.0, 11.5 Hz, 1H, NCH), 4.36(s, 1H, NH), 4.23—4.19(m, 2H, OCH₂), 3.37(dd, J=4.0, 13.5 Hz, 1H, NCCH), 2.83(dd, J=11.5, 13.5 Hz, 1H, NCCH), 1.28(t, J=7.5 Hz, 3H, CH₃)	172.67, 164.08(dd, J=12.12, 251.25 Hz), 161.64(dd, J=12.25, 250.88 Hz), 138.55, 137.61, 131.90(dd, J=4.88, 9.75 Hz), 128.57, 127.00, 124.71(dd, J=3.75, 11.88 Hz), 121.95, 121.61, 112.01(dd, J=3.25, 21.25 Hz), 104.35(t, J=26.00 Hz), 65.95, 61.83, 35.06, 35.01, 14.19
6a^b	7.78—6.70(m, 8H, PhH), 5.46(d, J=3.0 Hz, 1H, NH), 5.27—5.25(m, 1H, NCH), 4.11(dd, J=4.5, 9.5 Hz, 1H,SCH ), 3.62(s, 3H,OCH₃ ), 2.51—2.46(m, 1H, SCCH), 2.23—2.17(m, 1H, SCCH)	171.52, 160.85, 158.90, 150.15, 132.94, 129.95(d, J=13.38 Hz), 129.78(d, J=8.25 Hz), 129.65(d, J=3.75 Hz), 128.97, 125.01(d, J=2.88 Hz), 120.44(d, J=20.5 Hz), 119.20, 115.89(d, J=21.88 Hz), 52.79, 50.49, 43.80, 37.55
6b^c	7.45—6.77(m, 8H, PhH), 5.13—5.10(m, 1H, NCH), 4.85(s, 1H, NH), 4.07(dd, J=4.5, 9.5 Hz, 1H, SCH), 3.67(s, 3H, OCH₃), 2.50—2.45(m, 1H, SCCH), 2.41—2.36(m, 1H, SCCH)	171.24, 163.87, 161.93, 149.58, 146.41(d, J=7.00 Hz), 132.86, 130.41(d, J=8.12 Hz), 128.69, 123.03(d, J=2.75 Hz), 120.64, 120.01, 119.89, 114.14(d, J=18.12 Hz), 113.97(d, J=19.00 Hz), 56.98, 51.74, 43.12, 38.68
6c^c	7.94—6.78(m, 7H, PhH), 5.40—5.38(m, 1H, NCH), 4.87(s, 1H, NH), 4.08(t, J=10.0 Hz, 1H, SCH), 3.67(s, 3H, OCH₃), 2.57—2.52(m, 1H, SCCH), 2.36—2.31(m, 1H, SCCH)	171.16, 162.24(dd, J=12.12, 245.00 Hz), 160.02(dd, J=12.12, 246.62 Hz), 149.54, 132.82, 130.43(dd, J=6.00, 9.75 Hz), 128.70, 126.27(dd, J=3.62, 13.88 Hz), 120.73, 119.98, 119.87, 111.26(dd, J=3.38, 21.00 Hz), 103.60(t, J=26.00 Hz), 51.73, 50.26, 43.19, 36.93
6d^c	7.86—6.79(m, 8H, PhH), 5.48—5.47(m, 1H, NCH), 4.81(s, 1H, NH), 4.16—4.13(m, 3H, OCH₂, SCH), 2.60—2.54(m, 1H, SCCH), 2.39—2.34(m, 1H, SCCH), 1.23(t, J=7.0 Hz, 3H, CH₃)	170.60, 160.85, 158.90, 149.66, 132.72, 129.96(d, J=13.50 Hz), 129.30(d, J=8.62 Hz), 129.02(d, J=4.25 Hz), 128.53, 124.54(d, J=3.50 Hz), 120.60, 120.04, 119.98, 115.39(d, J=22.00 Hz), 60.89, 50.70, 43.81, 37.55, 13.55
6e^c	7.46—6.78(m, 8H, PhH), 5.12—5.10(m, 1H, NCH), 4.84(s, 1H, NH), 4.17—4.07(m, 2H, OCH₂), 4.04(dd, J=4.5, 10.0 Hz, 1H, SCH), 2.50—2.44(m, 1H, SCCH), 2.41—2.36(m, 1H, SCCH), 1.21(t, J=7.0 Hz, 3H, CH₃)	170.67, 163.87, 161.93, 149.66, 146.50(d, J=7.00 Hz), 132.92, 130.40(d, J=8.25 Hz), 128.65, 123,02(d, J=2.62 Hz), 120.62, 120.02, 114.11(d, J=17.25 Hz), 113.94(d, J=18.12 Hz), 60.84, 57.01, 43.28, 38.74, 13.53
6f^b	7.84—6.71(m, 7H, PhH), 5.48(d, J=3.0 Hz, 1H, NH), 5.18(d, J=9.0 Hz, 1H, NCH), 4.01—4.04(m, 2H, OCH₂), 4.02(dd, J=4.5, 9.5 Hz, 1H, SCH), 2.45(dd, J=9.0, 9.5 Hz, 1H, SCCH), 2.21—2.15(m, 1H, SCCH)	170.96, 162.04(dd, J=12.75, 244.38 Hz), 159.96(dd, J=12.62, 246.50 Hz), 133.13, 130.96(dd, J=6.00, 9.75 Hz), 129.06, 126.46(dd, J=3.38, 13.62 Hz), 120.62, 120.37, 119.31, 111.89(dd, J=3.00, 20.75 Hz), 104.35(t, J=25.88 Hz), 61.42, 50.10, 43.68, 37.23, 14.40
7a^a	8.07—7.08(m, 8H, PhH), 3.68(t, J=6.75 Hz, 2H, SCH₂), 2.94(t, J=6.75 Hz, 2H, SCCH₂)	169.73, 162.35, 160.36, 152.18, 134.77, 132.22(d, J=8.88 Hz), 130.79(d, J=3.25 Hz), 129.56, 127.32(d, J=11.62 Hz), 125.16(d, J=25.25 Hz), 124.54(d, J=3.25 Hz), 116.32(d, J=22.88 Hz), 41.19, 30.60
7b^a	7.72—7.00(m, 8H, PhH), 3.57(t, J=7.0 Hz, 2H, SCH₂), 2.88(t, J=7.0 Hz, 2H, SCCH₂)	169.71, 164.13, 162.17,152.75, 140.23(d, J=7.12 Hz), 134.83, 130.21(d, J=8.00 Hz), 129.66, 125.16(d, J=14.38 Hz), 123.35, 122.93(d, J=2.62 Hz), 117.89(d, J=21.50 Hz), 114.15(d, J=22.62 Hz), 41.65, 29.74
7c^a	8.13—6.88(m, 7H, PhH), 3.67(t, J=6.75 Hz, 2H, SCH₂), 2.91(t, J=6.75 Hz, 2H, SCCH₂)	168.49, 164.47(dd, J=12.25, 251.88 Hz), 161.68(dd, J=12.25, 251.75 Hz), 152.00, 134.79, 132.22(dd, J=4.75, 77.00 Hz), 129.62, 125.34, 125.01, 123.59(dd, J=3.62, 11.62 Hz), 112.08(dd, J=3.12, 21.00 Hz), 104.46(t, J=26.12 Hz), 41.17, 32.91

Table 5 Zone of growth inhibition of compounds 3a—3k(mm)a

Compd.	C.albicans ATCC10231	C.Neofonmans		Compd.	C.albicans ATCC10231	C.Neofonmans
Compd.	C.albicans ATCC10231	ATCC 34874	Clinical isolate	Compd.	C.albicans ATCC10231	ATCC 34874	Clinical isolate
3a	9.8	22.3	24.8	3h	6.0	6.0	15.7
3b	10.3	20.4	24.5	3i	6.0	6.0	6.0
3c	6.0	15.5	18.5	3j	6.0	6.0	12.2
3d	10.4	22.5	21.1	3k	6.0	6.0	6.0
3e	6.0	20.3	23.4	Control^b	6.0	6.0	6.0
3f	6.0	26.3	30.8	A	12.1	27.0	30.5
3g	6.0	6.0	18.4

Fig.2 Inhibition zones at different dose levels for compounds 3a(a), 3b(b), 3d—3f(c—e) against C. neoformans(ATCC34874)(A) and C. neoformans(clinical isolate)(B)

Table 6 MIC, MIC80 and MFC values for compounds 3a, 3b, 3d—3f and fluconazole(μg/mL)

Compd.	MIC		MIC₈₀		MFC
Compd.	1^a	2^a	1^a	2^a	1^a	2^a
3a	3.0	3.0	2.0	2.0	12.0	12.0
3b	4.0	3.0	2.0	2.0	12.0	14.0
3d	2.0	1.5	—^b	—^b	8.0	8.0
3e	2.0	2.0	1.0	1.0	10.0	8.0
3f	1.0	0.5	0.5	0.5	6.0	6.0
Fluconazole	>128.0	>128.0	2.0	3.0	>128.0	>128.0

Table 7 Zone of growth inhibition of compounds 4—7(mm)*

Compd.	C. Neofonmans		Compd.	C. Neofonmans
Compd.	ATCC34874	Clinical isolate	Compd.	ATCC34874	Clinical isolate
4a,4b,4d	6.0	6.0	5a	13.5	13.8
4c	14.1	13.4	5b—5f	6.0	6.0
4e	11.2	12.7	6a—6f	6.0	6.0
4f	15.5	13.1	7a—7c	6.0	6.0
A	27.0	30.5

参考文献 21

[1]	Nagao T., Sato M., Iwasawa Y., Takada T., Ishida R., Jpn. J. Pharmacol., 1972, 22, 467—478
[2]	Nagao T., Sato M., Nakajima H., Kiyomoto A., Chem. Pharm. Bull., 1973, 21(1), 92—97
[3]	Yamada K., Shimamura T., Nakajima H., Jpn. J. Pharmacol., 1973, 23, 321—328
[4]	Yamamoto H., Asai H., Chem. Pharm. Bull., 1986, 34(9), 3844—3853
[5]	Asano T., Okumura T., Hirano K., Adachi T., Sugiura M., Chem. Pharm. Bull., 1986, 34(10), 4238—4243
[6]	Ambrogi V., Furlani A., Grandolini G., Papaioannou A., Perioli L., Scarcia V., Tuttobello L., Eur. J. Med. Chem., 1993, 28, 659—667
[7]	Desai M. D., Desai K. K., Asian J. Chem., 2002, 14(2), 974—978
[8]	Kang W., Du X. Q., Wang L. Z., Hu L. J., Dong Y. H., Bian Y. Q., Li Y., Chin. J. Chem., 2013, 31, 1305—1314
[9]	Qing F. X., Chin. J. Org. Chem., 2012, 32, 815—824
	(卿凤翔. 有机化学, 2012, 32, 815—824)
[10]	Wang J., Liu H., Chin. J. Org. Chem., 2011, 31, 1785—1798
	(王江, 柳红. 有机化学, 2011, 31, 1785—1798
[11]	Guo Q., Liu B. Q., Guo H. Y., Chin. J. Pharm., 2008, 39(4), 297—303
	(郭强, 刘秉全, 郭慧元. 中国医药工业杂志, 2008, 39(4), 297—303)
[12]	Sang P., Zou J. W., Xu L., Huang G. D., Chem., 2009, 11, 973—978
	(桑鹏, 邹建卫, 许林, 黄光东. 化学通报, 2009, 11, 973—978)
[13]	Zhang J., Jin C. F., Zhang Y. J., Chin. J. Org. Chem., 2014, 34, 662—680
	(张霁, 金传飞, 张英俊. 有机化学, 2014, 34, 662—680)
[14]	Song Y., Wang J. C., Xu H., Zhang G. Z., Selim H. A., Li G. S., Wang Q., Gao Z. L., Chem. Res. Chinese Universities, 2013, 29(2), 263—269
[15]	Zhang W.S., Li A. L., Medicinal Chemistry, Higher Education Press, Beijing, 1999, 545—553
	(仉文升, 李安良. 药物化学, 北京:高等教育出版社, 1999, 545—553)
[16]	Jiang X. L., Cui Y. B., Cao S. H., Chin. J. Antibiot., 2011, 36(4), 255—263
	(蒋晓磊, 崔玉彬, 曹胜华. 中国抗生素杂志, 2011, 36(4), 255—263)
[17]	Wan K., Zhang Y. Y., Zhou C. H., Zhou X. D., Geng R. X., Ji Q. G., Chin. J. Antibiot., 2012, 37(1), 8—15
	(万昆, 张奕奕, 周成合, 周向东, 耿蓉霞, 吉庆刚. 中国抗生素杂志, 2012, 37(1), 8—15)
[18]	Wang A. P., Li R. Y., Chin. J. Mycol., 2010, 5(1), 44—47
	(王爱平, 李若瑜. 中国真菌学杂志, 2010, 5(1), 44—47)
[19]	Tang L. S., J. Univ. Sci. Technol. Qingdao(Natural Science Edition), 2008, 29(2), 98—100
	(唐林生. 青岛科技大学学报(自然科学版), 2008, 29(2), 98—100)
[20]	Li W. H., Liu X. Y., Zhang B., Li Y., Chin. J. Org. Chem., 2013, 33, 1503—1508
	(李文红, 刘喜莹, 张博, 李媛. 有机化学, 2013, 33, 1503—1508)
[21]	Kang W., Bu H. J., Li W. H., Li Y., Chem. J. Chinese Universities, 2014, 35(4), 766—775
	(康旺, 卜辉娟, 李文红, 李媛. 高等学校化学学报, 2014, 35(4), 766—775)