Design, Synthesis and Biological Activity of Novel Substituted Phenyl Oxazol Based Compounds†

doi:10.7503/cjcu20130551

Abstract

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

CLC Number:

O626

TrendMD:

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

Figures/Tables 5

References 23

[1]	Zhang H. Z., Zhou C. H., Geng R. X., Ji Q. G., Chin. J. Org. Chem., 2011, 31(12), 1963—1976
	(张慧珍, 周成合, 耿蓉霞, 吉庆刚.有机化学,2011, 31(12), 1963—1976)
[2]	Wang Z.N., Hu D. Y., Song B. A., Yang S., Jin L. H., Fine Chemical Intermediates, 2008, 38(2), 9—15
	(王振宁, 胡德禹, 宋宝安, 杨松, 金林红.精细化工中间体,2008, 38(2), 9—15)
[3]	Tomer I., Mishra R., Priyanka Sharma N. K., Keshari K. J., J. Pharm. Res., 2011, 4(9), 2975—2980
[4]	Hartmann-Thompson C., Keeley D. L., Pollock K. M., Dvomic P. R., Keinath S. E., Dantus M., Gunaratne T. C., Lecaptain D., J. Chem. Mater., 2008, 20, 2829
[5]	Zhao Q. Q., Liu S. H., Li Y. H., Wang Q. M., J. Agric. Food Chem., 2009, 57, 2849—2855
[6]	Lu X. Y., Liu X. B., Wan B. J., Franzblau S. G., Chen L. L., Zhou C. L., You Q. D., Eur. J. Med. Chem., 2012, 49, 164—171
[7]	Sun D. L., Li L., Ji R., Li W., Ye H. C., Wu Y. J., Liu C. L., B. Environ. Contam. Tox., 2011, 87(6), 653—656
[8]	Angioni A., Porcu L., Dedola F., Pest Manag. Sci., 2012, 68(4), 543—547
[9]	Chang K. C., Yew W. W., Cheung S. W., Leung C. C., Tam C. M., Chau C. H., Wen P. K., Chan R. C., Antimicrob. Agents. Ch., 2013, 57(7), 3445—3449
[10]	Xu G. Y., Zhou Y., Yang C. H., Xie Y. Y., Heteroatom. Chem., 2008, 19(3), 316—319
[11]	Kang T. N., Ling Y., Rui C. H., Yang X. L., Fan X. L., Chen F. H., Chin. J. Org. Chem., 2008, 28(4), 617—621
	(康铁牛, 凌云, 芮昌辉, 杨新玲, 范贤林, 陈馥衡.有机化学,2008, 28(4), 617—621)
[12]	Qiu N., Luo Y. F., Progress in Pharm. Sci., 2007, 31(10), 439—446
	(邱能, 罗有福.药学进展,2007, 31(10), 439—446)
[13]	Tomizawa M., Casida J. E., Toxicol. Appl. Pharmacol., 2000, 169, 114—120
[14]	Kagabu S., Nishimura K., Naruse Y., Ohno I., J. Pestic. Sci., 2008, 33, 58—66
[15]	Einsiedel J., Thomas C., Hubner H., Gmeiner P., Bioorg. Med. Chem.Lett., 2000, 10, 2041—2044
[16]	O’Mant D. M., Oxazole Derivatives, GB 1139940A, 1969-01-15
[17]	Simiti I., Chindris E., Archiv der Pharmazie und Berichte der Deutschen Pharmazeutischen Gesellschaft, 1971, 304, 425—429
[18]	Simiti I., Chindris E., Archiv der Pharmazie, 1972, 305, 509—515
[19]	Bossenmaier B., Friebe W. G., Reiff U., Rueth M., Voss E., 1'-(E)-2-(phenyl)ethenyl-4-(arylalkoxy)-oxazole or-thiazole Compounds as Her-2 Tyrosine Kinases Inhibitors and Their Use in the Treatment of Cancer, WO 2005040158A1, 2005-05-06
[20]	Chen B. K., Process for the Preparation of Heterocyclic Diamine Single-sided Condensation Products, US 20040210054A1, 2004-10-21
[21]	Chen N.C., Bioassay of Pesticides, Beijing Agricultural University Press, Beijing, 1991, 161
	(陈年春. 农药生物测定技术, 北京: 北京农业大学出版社, 1991, 161)
[22]	Liu S. H., Ling Y., Yang X. L., Chin. J. Struct. Chem., 2013, 32(6), 931—935
	(刘少华, 凌云, 杨新玲.结构化学,2013, 32(6), 931—935)
[23]	Shang J., Sun R. F., Li Y. Q., Huang R. Q., Bi F. C., Wang Q. M., J. Agric. Food Chem., 2010, 58, 1834—1837

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)