Design, synthesis and anti-fungal activity of 1,2,4-oxadiazole derivatives

doi:10.11949/0438-1157.20221365

Abstract

Abstract:

Soybean rust is one of the main fungal diseases affecting soybean production. To develop novel and highly effective fungicide, N-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)phenyl)cyclopropanecarboxamide was used as the lead compound. Using the method of structural modification and introducing new substituents, 12 new 1,2,4-oxadiazole derivatives were designed, synthesized through oximation, ring closure, reduction and condensation reactions. Their chemical structures were characterized by ¹H NMR and ESI-MS. The bioassay results showed that the inhibition rates of compounds 5b, 5d, 6a, 6e and 6g against soybean rust at the concentration of 3.125 mg/L were 60%, 65%, 100%, 98% and 95%, respectively. The activities were all better than that of control agent difenoconazole (50%). Compound 6a displayed prominent anti-fungal activity. When the mass concentration was 0.39125 mg/L, it still had 90% inhibition rate against soybean rust. The molecular docking results showed that compound 6a had various interactions with histone deacetylase 4(HDAC4) and histone deacetylase 7(HDAC7).

Key words: soybean rust, 1,2,4-oxadiazole, design, reaction, synthesis, anti-fungal activity, molecular docking

摘要：

大豆锈病是危害大豆生产的主要真菌病害。为了研发新型高效的杀菌剂，以N-(4-(5-(三氟甲基)-1，2，4-𫫇二唑-3-基)苯基)环丙甲酰胺为先导化合物，采用结构修饰的方法，引入新的取代基，以此设计了12个新型1，2，4-𫫇二唑类衍生物，通过肟化、合环、还原及缩合反应，合成得到，经¹H NMR和ESI-MS确证化学结构。测试了它们对大豆锈病的抗菌活性：当质量浓度为3.125 mg/L时，化合物5b、5d、6a、6e和6g对大豆锈病的抑制率分别为60%、65%、100%、98%和95%，优于对照药剂苯醚甲环唑(50%)；化合物6a抗菌活性优异，当质量浓度为0.39125 mg/L时，对大豆锈病仍有90%抑制率。分子对接的结果说明，化合物6a与组蛋白去乙酰化酶4(HDAC 4)和组蛋白去乙酰化酶7(HDAC 7)有着多种相互作用。

关键词: 大豆锈病, 1, 2, 4-??二唑, 设计, 反应, 合成, 抗菌活性, 分子对接

CLC Number:

TQ 455.4

Feng WANG, Yu CHEN, Hongyan PEI, Dongdong LIU, Jing ZHANG, Lixin ZHANG. Design, synthesis and anti-fungal activity of 1,2,4-oxadiazole derivatives[J]. CIESC Journal, 2023, 74(3): 1390-1398.

王锋, 陈钰, 裴鸿艳, 刘东东, 张静, 张立新. 1，2，4-𫫇二唑类衍生物的设计、合成及抗菌活性[J]. 化工学报, 2023, 74(3): 1390-1398.

Figures/Tables 11

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Compound	Reaction time/h	Feature	Melting point/℃	Yield/%	m/z (calcd.)^①
5a	4.0	white solid	185.2—185.9	75.65	340.1(340.1)
5b	4.0	white solid	188.2—189.0	78.25	354.1(354.1)
5c	3.5	yellow solid	184.6—185.2	76.52	368.1(368.1)
5d	5.0	yellow oil	—	70.26	352.2(352.1)
5e	5.0	white solid	189.6—190.1	72.24	370.1(370.1)

Compound	Reaction time/h	Feature	Melting point/℃	Yield/%	m/z (calcd.)^①
5a	4.0	white solid	185.2—185.9	75.65	340.1(340.1)
5b	4.0	white solid	188.2—189.0	78.25	354.1(354.1)
5c	3.5	yellow solid	184.6—185.2	76.52	368.1(368.1)
5d	5.0	yellow oil	—	70.26	352.2(352.1)
5e	5.0	white solid	189.6—190.1	72.24	370.1(370.1)

Compound	δ
5a	8.23 (d, J = 8.5 Hz, 2H, Ph-2H), 7.39 (d, J = 8.5 Hz, 2H, Ph-2H), 2.51 (s, 3H, CH₃), 1.63—1.59 (m, 1H, CH), 1.18—1.11 (m, 2H, half-CH₂CH₂), 0.86—0.83 (m, 2H, half-CH₂CH₂)
5b	8.23 (d, J = 8.5 Hz, 2H, Ph-2H), 7.38 (d, J = 8.5 Hz, 2H, Ph-2H), 2.80 (q, J = 7.3 Hz, 2H, CH₂), 1.75—1.71 (m, 1H, CH), 1.17 (t, J = 7.3 Hz, 3H, CH₃), 1.15—1.12 (m, 2H, half-CH₂CH₂), 0.87—0.84 (m, 2H, half-CH₂CH₂)
5c	8.22 (d, J = 8.4 Hz, 2H, Ph-2H), 7.36 (d, J = 8.5 Hz, 2H, Ph-2H), 3.35—3.30 (m, 1H, CH), 1.74—1.70 (m, 1H, CH), 1.21[d, J = 6.8 Hz, 6H, (CH₃)₂], 1.17—1.14 (m, 2H, half-CH₂CH₂), 0.88—0.85 (m, 2H, half-CH₂CH₂)
5d	8.23 (d, J = 8.4 Hz, 2H, Ph-2H), 7.39 (d, J = 8.5 Hz, 2H, Ph-2H), 6.63 (dd, J = 16.8, 10.3 Hz, 1H, =CH), 6.48 (dd, J = 16.8, 1.6 Hz, 1H, CH), 5.78 (dd, J = 10.3, 1.6 Hz, 1H, =CH), 1.93—1.89 (m, 1H, CH), 1.21—1.18 (m, 2H, half-CH₂CH₂), 0.94—0.91 (m, 2H, half-CH₂CH₂)
5e	8.17 (d, J = 8.5 Hz, 2H, Ph-2H), 7.30 (d, J = 8.5 Hz, 2H, Ph-2H), 4.23 (q, J = 7.1 Hz, 2H, CH₂), 2.83—2.78 (m, 1H, CH), 1.20 (t, J = 7.1 Hz, 3H, CH₃), 1.19—1.16 (m, 2H, half-CH₂CH₂), 1.02—0.99 (m, 2H, half-CH₂CH₂)

Compound	δ
5a	8.23 (d, J = 8.5 Hz, 2H, Ph-2H), 7.39 (d, J = 8.5 Hz, 2H, Ph-2H), 2.51 (s, 3H, CH₃), 1.63—1.59 (m, 1H, CH), 1.18—1.11 (m, 2H, half-CH₂CH₂), 0.86—0.83 (m, 2H, half-CH₂CH₂)
5b	8.23 (d, J = 8.5 Hz, 2H, Ph-2H), 7.38 (d, J = 8.5 Hz, 2H, Ph-2H), 2.80 (q, J = 7.3 Hz, 2H, CH₂), 1.75—1.71 (m, 1H, CH), 1.17 (t, J = 7.3 Hz, 3H, CH₃), 1.15—1.12 (m, 2H, half-CH₂CH₂), 0.87—0.84 (m, 2H, half-CH₂CH₂)
5c	8.22 (d, J = 8.4 Hz, 2H, Ph-2H), 7.36 (d, J = 8.5 Hz, 2H, Ph-2H), 3.35—3.30 (m, 1H, CH), 1.74—1.70 (m, 1H, CH), 1.21[d, J = 6.8 Hz, 6H, (CH₃)₂], 1.17—1.14 (m, 2H, half-CH₂CH₂), 0.88—0.85 (m, 2H, half-CH₂CH₂)
5d	8.23 (d, J = 8.4 Hz, 2H, Ph-2H), 7.39 (d, J = 8.5 Hz, 2H, Ph-2H), 6.63 (dd, J = 16.8, 10.3 Hz, 1H, =CH), 6.48 (dd, J = 16.8, 1.6 Hz, 1H, CH), 5.78 (dd, J = 10.3, 1.6 Hz, 1H, =CH), 1.93—1.89 (m, 1H, CH), 1.21—1.18 (m, 2H, half-CH₂CH₂), 0.94—0.91 (m, 2H, half-CH₂CH₂)
5e	8.17 (d, J = 8.5 Hz, 2H, Ph-2H), 7.30 (d, J = 8.5 Hz, 2H, Ph-2H), 4.23 (q, J = 7.1 Hz, 2H, CH₂), 2.83—2.78 (m, 1H, CH), 1.20 (t, J = 7.1 Hz, 3H, CH₃), 1.19—1.16 (m, 2H, half-CH₂CH₂), 1.02—0.99 (m, 2H, half-CH₂CH₂)

Compound	Reaction time/h	Feature	Melting point/℃	Yield/%	m/z (calcd.)
6a	4.0	white solid	185.2—185.6	80.45	365.2(365.1)
6b	5.0	white solid	190.5—191.2	80.25	338.4(338.1)
6c	4.0	yellow solid	162.6—163.7	90.84	360.3(360.1)
6d	5.0	white solid	184.2—185.2	84.52	380.3(380.1)
6e	5.0	white solid	183.5—184.2	73.69	384.2(384.1)
6f	5.0	white solid	195.2—195.8	80.42	380.2(380.1)
6g	5.0	white solid	248.6—249.0	70.35	384.1(384.1)