新型取代苯基噁唑类化合物的设计、 合成及生物活性

doi:10.7503/cjcu20130551

摘要/Abstract

摘要：

通过活性亚结构拼接方法, 将具有生物活性的噁唑基团与咪唑烷或噻唑烷拼接, 设计合成了一系列新型取代苯基噁唑类化合物. 以取代的苯甲酸为原料, 经过3步反应制得目标化合物, 其结构经核磁共振及元素分析确证. 初步生物测定结果表明, 部分化合物对小麦赤霉病、水稻纹枯病、黄瓜灰霉病和番茄早疫病表现出明显的抑制活性, 尤其是化合物 5q表现出较广的杀菌谱, 且活性与多氧霉素相当. 初步构效关系分析发现, 苯环上取代基的类别和位置对活性有影响, 其中卤素取代基对活性有利, 邻位取代优于对位和间位取代.

关键词: 噁唑, 咪唑烷, 噻唑烷, 生物活性

Abstract:

Several famous bioactive heterocycles such as oxazole, imidazolidine and thiazolidine are widely used in both pharmaceutical and pesticide industry. To find new lead compounds with favorable biological activities, a series of novel substituted phenyl oxazol based compounds containing 2-nitroaminoimidazoline or thiazolidine was designed via the method of linking active sub-structures. The target compounds were synthesized from substituted benzoic acid in three steps. Their structures were confirmed by ¹H NMR and elemental analysis. The preliminary bioassay results indicated that some target compounds showed obvious inhibitory activities against Gibberella saubinetii, Rhizoctonia solani, Botrytis cinerea and Alternaria solan. Especially, compound 5q, with 62% and 86% inhibition rate against Gibberella saubinetii and Botrytis cinerea, respectively, exhibited equivalent activity to Polyoxin B with 57% and 85% inhibition rate at a concentration of 100 μg/mL. The structure-activity relationship indicated that the type and position of substituent on the benzene ring would influence the activity obviously. The halogen substituent was favorable to activity. Besides, compounds with ortho-substituent showed better activity than those with meta or para-substituent.

Key words: Oxazole, Imidazoline, Thiazolidine, Biological activity

中图分类号:

O626

TrendMD:

刘少华, 凌云, 李宏月, 徐丹, 杨新玲. 新型取代苯基噁唑类化合物的设计、合成及生物活性. 高等学校化学学报, 2014, 35(2): 281.

LIU Shaohua, LING Yun, LI Hongyue, XU Dan, YANG Xinling. Design, Synthesis and Biological Activity of Novel Substituted Phenyl Oxazol Based Compounds^†. Chem. J. Chinese Universities, 2014, 35(2): 281.

图/表 5

参考文献 23

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Compd.	Appearance	m.p./℃	Yield(%)	Elemental analysis(calcd.)(%)
Compd.	Appearance	m.p./℃	Yield(%)	C	H	N
5a	White solid	139—140	69.1	54.10(54.35)	4.70(4.56)	24.32(24.38)
5b	White solid	151—152	58.8	48.58(48.53)	3.72(3.76)	21.84(21.77)
5c	White solid	150—152	62.4	55.74(55.81)	4.97(5.02)	23.41(23.24)
5d	White solid	156—158	62.0	42.59(42.64)	3.27(3.30)	19.23(19.13)
5e	Yellow solid	226—228	48.1	46.78(46.99)	3.64(3.64)	25.31(25.29)
5f	White solid	200—201	58.1	52.99(52.99)	4.77(4.76)	22.16(22.07)
5g	White solid	142—144	60.2	48.48(48.53)	3.76(3.76)	21.89(21.77)
5h	White solid	104—106	61.3	48.45(48.53)	3.67(3.76)	21.87(21.77)
5i	White solid	141—142	61.4	51.25(51.15)	3.97(3.96)	23.18(22.94)
5j	White solid	120—121	68.5	59.14(59.14)	4.21(4.25)	19.69(19.70)
5k	White solid	154—156	69.1	52.76(52.75)	3.45(3.48)	17.59(17.58)
5l	White solid	136—138	69.8	60.25(60.38)	4.73(4.73)	18.68(18.78)
5m	White solid	155—156	70.0	46.29(46.29)	3.04(3.05)	15.50(15.42)
5n	Yellow solid	198—200	49.0	50.92(51.06)	3.47(3.37)	21.32(21.27)
5o	White solid	144—146	69.2	57.13(57.31)	4.49(4.49)	17.89(17.82)
5p	White solid	122—124	67.8	52.75(52.75)	3.55(3.48)	17.70(17.58)
5q	White solid	121—122	68.4	52.75(52.75)	3.47(3.48)	17.78(17.58)
5r	White solid	118—119	69.0	55.73(55.62)	3.70(3.67)	18.63(18.53)

Compd.	Appearance	m.p./℃	Yield(%)	Elemental analysis(calcd.)(%)
Compd.	Appearance	m.p./℃	Yield(%)	C	H	N
5a	White solid	139—140	69.1	54.10(54.35)	4.70(4.56)	24.32(24.38)
5b	White solid	151—152	58.8	48.58(48.53)	3.72(3.76)	21.84(21.77)
5c	White solid	150—152	62.4	55.74(55.81)	4.97(5.02)	23.41(23.24)
5d	White solid	156—158	62.0	42.59(42.64)	3.27(3.30)	19.23(19.13)
5e	Yellow solid	226—228	48.1	46.78(46.99)	3.64(3.64)	25.31(25.29)
5f	White solid	200—201	58.1	52.99(52.99)	4.77(4.76)	22.16(22.07)
5g	White solid	142—144	60.2	48.48(48.53)	3.76(3.76)	21.89(21.77)
5h	White solid	104—106	61.3	48.45(48.53)	3.67(3.76)	21.87(21.77)
5i	White solid	141—142	61.4	51.25(51.15)	3.97(3.96)	23.18(22.94)
5j	White solid	120—121	68.5	59.14(59.14)	4.21(4.25)	19.69(19.70)
5k	White solid	154—156	69.1	52.76(52.75)	3.45(3.48)	17.59(17.58)
5l	White solid	136—138	69.8	60.25(60.38)	4.73(4.73)	18.68(18.78)
5m	White solid	155—156	70.0	46.29(46.29)	3.04(3.05)	15.50(15.42)
5n	Yellow solid	198—200	49.0	50.92(51.06)	3.47(3.37)	21.32(21.27)
5o	White solid	144—146	69.2	57.13(57.31)	4.49(4.49)	17.89(17.82)
5p	White solid	122—124	67.8	52.75(52.75)	3.55(3.48)	17.70(17.58)
5q	White solid	121—122	68.4	52.75(52.75)	3.47(3.48)	17.78(17.58)
5r	White solid	118—119	69.0	55.73(55.62)	3.70(3.67)	18.63(18.53)

Compd.	¹H NMR(300 MHz, CDCl₃), δ
5a	3.60—3.64(m, 4H), 4.44(s, 2H, CH₂), 7.53—7.55(m, 3H, Ar—H), 7.96—7.99(m, 2H, Ar—H), 8.20(s, 1H, Ar—H), 8.97(s, 1H, NH)
5b	3.79—3.82(m, 4H), 4.51(s, 2H, CH₂), 7.44(d, ³J_HH=8.7 Hz, 2H, Ar—H), 7.50(s, 1H, Ar—H), 7.95(d, ³J_HH=8.7 Hz, 2H, Ar—H), 8.13(s, 1H, NH)
5c	2.37(s, 3H, CH₃), 3.60—3.64(m, 4H), 4.41(s, 2H, CH₂), 7.34(d, ³J_HH=8.1 Hz, 2H, Ar—H), 7.86(d, ³J_HH=8.1 Hz, 2H, Ar—H), 8.15(s, 1H, Ar—H), 8.96(s, 1H, NH)
5d	3.59—3.63(m, 4H), 4.42(s, 2H, CH₂), 7.44(d, ³J_HH=8.7 Hz, 2H, Ar—H), 7.90(d, ³J_HH=8.7 Hz, 2H, Ar—H), 8.23(s, 1H, Ar—H), 8.96(s, 1H, NH)
5e	3.59—3.65(m, 4H), 4.47(s, 2H, CH₂), 8.21(d, ³J_HH=8.7 Hz, 2H, Ar—H), 8.36—8.39(m, 3H, Ar—H), 8.98(s, 1H, NH)
5f	3.59—3.63(m, 4H), 3.83(s, 3H), 4.40(s, 2H, CH₂), 7.08(d, ³J_HH=8.7 Hz, 2H, Ar—H), 7.91(d, ³J_HH=8.7 Hz, 2H, Ar—H), 8.12(s, 1H, Ar—H), 8.97(s, 1H, NH)
5g	3.61—3.65(m, 4H), 4.43(s, 2H, CH₂), 7.57—7.63(m, 2H, Ar—H), 7.91—7.95(m, 2H, Ar—H), 8.25(s, 1H, Ar—H), 8.98(s, 1H, NH)
5h	3.62—3.64(m, 4H), 4.45(s, 2H, CH₂), 7.50—7.59(m, 2H, Ar—H), 7.63—7.67(m, 1H, Ar—H), 7.95—7.98(m, 1H, Ar—H), 8.25(s, 1H, Ar—H), 8.97(s, 1H, NH)
5i	3.59—3.63(m, 4H), 4.42(s, 2H, CH₂), 7.35—7.41(m, 2H, Ar—H), 8.00—8.05(m, 2H, Ar—H), 8.20(s, 1H, Ar—H), 8.97(s, 1H, NH)
5j	3.51(t, ³J_HH=7.8 Hz, 2H, CH₂), 4.03(t, ³J_HH=7.8 Hz, 2H, CH₂), 4.60(s, 2H, CH₂), 7.54—7.57(m, 3H, Ar—H), 7.97—8.00(m, 2H, Ar—H), 8.24(s, 1H, Ar—H)
5k	3.50(t, ³J_HH=7.8 Hz, 2H, CH₂), 4.04(t, ³J_HH=7.8 Hz, 2H, CH₂), 4.59(s, 2H, CH₂), 7.61(d, ³J_HH=8.7 Hz, 2H, Ar—H), 7.78(d, ³J_HH=8.7 Hz, 2H, Ar—H), 8.27(s, 1H, Ar—H)
5l	2.37(s, 3H, CH₃), 3.50(t, ³J_HH=7.8 Hz, 2H, CH₂), 4.01(t, ³J_HH=7.8 Hz, 2H, CH₂), 4.57(s, 2H, CH₂), 7.35(d, ³J_HH=8.7 Hz, 2H, Ar—H), 7.86(d, ³J_HH=8.7 Hz, 2H, Ar—H), 8.20(s, 1H, Ar—H)
5m	3.51(t, ³J_HH=7.8 Hz, 2H, CH₂), 4.01(t, ³J_HH=7.8 Hz, 2H, CH₂), 4.59(s, 2H, CH₂), 7.75(d, ³J_HH=8.7 Hz, 2H, Ar—H), 7.91(d, ³J_HH=8.7 Hz, 2H, Ar—H), 8.27(s, 1H, Ar—H)
5n	3.51(t, ³J_HH=7.8 Hz, 2H, CH₂), 4.03(t, ³J_HH=7.8 Hz, 2H, CH₂), 4.63(s, 2H, CH₂), 8.22(d, ³J_HH=8.7 Hz, 2H, Ar—H), 8.36—8.39(m, 3H, Ar—H)
5o	3.83(s, 3H), 4.00(t, ³J_HH=7.2 Hz, 2H, CH₂), 4.36(t, ³J_HH=5.1 Hz, 2H, CH₂), 4.56(s, 2H, CH₂), 7.09(d, ³J_HH=8.7 Hz, 2H, Ar—H), 7.91(d, ³J_HH=8.7 Hz, 2H, Ar—H), 8.16(s, 1H, Ar—H)
5p	3.51(t, ³J_HH=7.8 Hz, 2H, CH₂), 4.02(t, ³J_HH=7.8 Hz, 2H, CH₂), 4.59(s, 2H, CH₂), 7.55—7.65(m, 2H, Ar—H), 7.92—7.94(m, 2H, Ar—H), 8.29(s, 1H, Ar—H)
5q	3.51(t, ³J_HH=7.8 Hz, 2H, CH₂), 4.06(t, ³J_HH=7.8 Hz, 2H, CH₂), 4.62(s, 2H, CH₂), 7.46—7.57(m, 2H, Ar—H), 7.60—7.63(m, 1H, Ar—H), 7.95—7.99(m, 1H, Ar—H), 8.28(s, 1H, Ar—H)
5r	3.50(t, ³J_HH=7.8 Hz, 2H, CH₂), 4.01(t, ³J_HH=7.8 Hz, 2H, CH₂), 4.58(s, 2H, CH₂), 7.36—7.42(m, 2H, Ar—H), 8.00—8.05(m, 2H, Ar—H), 8.24(s, 1H, Ar—H)

Compd.	¹H NMR(300 MHz, CDCl₃), δ
5a	3.60—3.64(m, 4H), 4.44(s, 2H, CH₂), 7.53—7.55(m, 3H, Ar—H), 7.96—7.99(m, 2H, Ar—H), 8.20(s, 1H, Ar—H), 8.97(s, 1H, NH)
5b	3.79—3.82(m, 4H), 4.51(s, 2H, CH₂), 7.44(d, ³J_HH=8.7 Hz, 2H, Ar—H), 7.50(s, 1H, Ar—H), 7.95(d, ³J_HH=8.7 Hz, 2H, Ar—H), 8.13(s, 1H, NH)
5c	2.37(s, 3H, CH₃), 3.60—3.64(m, 4H), 4.41(s, 2H, CH₂), 7.34(d, ³J_HH=8.1 Hz, 2H, Ar—H), 7.86(d, ³J_HH=8.1 Hz, 2H, Ar—H), 8.15(s, 1H, Ar—H), 8.96(s, 1H, NH)
5d	3.59—3.63(m, 4H), 4.42(s, 2H, CH₂), 7.44(d, ³J_HH=8.7 Hz, 2H, Ar—H), 7.90(d, ³J_HH=8.7 Hz, 2H, Ar—H), 8.23(s, 1H, Ar—H), 8.96(s, 1H, NH)
5e	3.59—3.65(m, 4H), 4.47(s, 2H, CH₂), 8.21(d, ³J_HH=8.7 Hz, 2H, Ar—H), 8.36—8.39(m, 3H, Ar—H), 8.98(s, 1H, NH)
5f	3.59—3.63(m, 4H), 3.83(s, 3H), 4.40(s, 2H, CH₂), 7.08(d, ³J_HH=8.7 Hz, 2H, Ar—H), 7.91(d, ³J_HH=8.7 Hz, 2H, Ar—H), 8.12(s, 1H, Ar—H), 8.97(s, 1H, NH)
5g	3.61—3.65(m, 4H), 4.43(s, 2H, CH₂), 7.57—7.63(m, 2H, Ar—H), 7.91—7.95(m, 2H, Ar—H), 8.25(s, 1H, Ar—H), 8.98(s, 1H, NH)
5h	3.62—3.64(m, 4H), 4.45(s, 2H, CH₂), 7.50—7.59(m, 2H, Ar—H), 7.63—7.67(m, 1H, Ar—H), 7.95—7.98(m, 1H, Ar—H), 8.25(s, 1H, Ar—H), 8.97(s, 1H, NH)
5i	3.59—3.63(m, 4H), 4.42(s, 2H, CH₂), 7.35—7.41(m, 2H, Ar—H), 8.00—8.05(m, 2H, Ar—H), 8.20(s, 1H, Ar—H), 8.97(s, 1H, NH)
5j	3.51(t, ³J_HH=7.8 Hz, 2H, CH₂), 4.03(t, ³J_HH=7.8 Hz, 2H, CH₂), 4.60(s, 2H, CH₂), 7.54—7.57(m, 3H, Ar—H), 7.97—8.00(m, 2H, Ar—H), 8.24(s, 1H, Ar—H)
5k	3.50(t, ³J_HH=7.8 Hz, 2H, CH₂), 4.04(t, ³J_HH=7.8 Hz, 2H, CH₂), 4.59(s, 2H, CH₂), 7.61(d, ³J_HH=8.7 Hz, 2H, Ar—H), 7.78(d, ³J_HH=8.7 Hz, 2H, Ar—H), 8.27(s, 1H, Ar—H)
5l	2.37(s, 3H, CH₃), 3.50(t, ³J_HH=7.8 Hz, 2H, CH₂), 4.01(t, ³J_HH=7.8 Hz, 2H, CH₂), 4.57(s, 2H, CH₂), 7.35(d, ³J_HH=8.7 Hz, 2H, Ar—H), 7.86(d, ³J_HH=8.7 Hz, 2H, Ar—H), 8.20(s, 1H, Ar—H)
5m	3.51(t, ³J_HH=7.8 Hz, 2H, CH₂), 4.01(t, ³J_HH=7.8 Hz, 2H, CH₂), 4.59(s, 2H, CH₂), 7.75(d, ³J_HH=8.7 Hz, 2H, Ar—H), 7.91(d, ³J_HH=8.7 Hz, 2H, Ar—H), 8.27(s, 1H, Ar—H)
5n	3.51(t, ³J_HH=7.8 Hz, 2H, CH₂), 4.03(t, ³J_HH=7.8 Hz, 2H, CH₂), 4.63(s, 2H, CH₂), 8.22(d, ³J_HH=8.7 Hz, 2H, Ar—H), 8.36—8.39(m, 3H, Ar—H)
5o	3.83(s, 3H), 4.00(t, ³J_HH=7.2 Hz, 2H, CH₂), 4.36(t, ³J_HH=5.1 Hz, 2H, CH₂), 4.56(s, 2H, CH₂), 7.09(d, ³J_HH=8.7 Hz, 2H, Ar—H), 7.91(d, ³J_HH=8.7 Hz, 2H, Ar—H), 8.16(s, 1H, Ar—H)
5p	3.51(t, ³J_HH=7.8 Hz, 2H, CH₂), 4.02(t, ³J_HH=7.8 Hz, 2H, CH₂), 4.59(s, 2H, CH₂), 7.55—7.65(m, 2H, Ar—H), 7.92—7.94(m, 2H, Ar—H), 8.29(s, 1H, Ar—H)
5q	3.51(t, ³J_HH=7.8 Hz, 2H, CH₂), 4.06(t, ³J_HH=7.8 Hz, 2H, CH₂), 4.62(s, 2H, CH₂), 7.46—7.57(m, 2H, Ar—H), 7.60—7.63(m, 1H, Ar—H), 7.95—7.99(m, 1H, Ar—H), 8.28(s, 1H, Ar—H)
5r	3.50(t, ³J_HH=7.8 Hz, 2H, CH₂), 4.01(t, ³J_HH=7.8 Hz, 2H, CH₂), 4.58(s, 2H, CH₂), 7.36—7.42(m, 2H, Ar—H), 8.00—8.05(m, 2H, Ar—H), 8.24(s, 1H, Ar—H)