Design, synthesis and fungicidal activities of Thiasporine A analogues
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摘要: Thiasporine A是从海洋放线菌Actinomycetospora chlora SNC-032代谢物中分离得到一个含有苯基噻唑环结构的天然产物，对肺癌细胞系H2122具有中等毒性。本文以取代苯甲腈为原料合成了Thiasporine A ( 4o ) 和29个Thiasporine A类似物( 3a ~ 3o ， 4a ~ 4n )，其中24个未见文献报道, 利用 核磁共振氢谱、碳谱和高分辨质谱对化合物的结构进行了表征，并测定了Thiasporine A及其类似物的抑菌活性。结果表明，在200 μmol/L的浓度下，大部分目标化合物对5种供试植物病原真菌均有一定的抑制效果。其中：化合物 3e 和 3i 对水稻纹枯病菌Rhizoctonia solani的抑制率分别为84.5%和84.4%，其EC50值分别为17.3 μmol/L和21.9 μmol/L；化合物 4b 和 4j 对白芨白绢病菌Selerotium rolfsii的抑制率为100%；化合物 4b 对烟草黑胫病菌Phytophthora parasitica抑制率为83.3%，高于商品药剂噻呋酰胺；化合物 3g 对5种供试病原菌的抑制率都在70%以上。Abstract: Thiasporine A was a natural product containing phenylthiazole ring isolated from the marine-derived Actinomycetospora chlora SNC-032 and showed cytotoxicity against the lung cancer cell line H2122. Thiasporine A ( 4o ) and 29 Thiasporine A analogues ( 3a - 3o , 4a - 4n ) were synthesized using substituted benzonitriles as starting material, among which 24 analogues have not been reported in literature. Their structures were characterized by 1H NMR, 13C NMR and HRMS spectra. The fungicidal activities of Thiasporine A and its analogues were tested. The results indicated that most of Thiasporine A analogues exhibited certain fungicidal activities. Compounds 3e and 3i were found to have the inhibition rates of 84.5% and 84.4% against Rhizoctonia solani at a concentration of 200 μmol/L, with the EC50 values of 17.3 μmol/L and 21.9 μmol/L, respectively. Compounds 4b and 4j displayed the inhibition rate of 100% against Selerotium rolfsii at 200 μmol/L. compound 4b demonstrated an inhibition rate of 83.3% against Phytophthora parasitica at 200 μmol/L, which was better than the commercial thifluzamide. The inhibition rates of compound 3g against five fungi were all higher than 70% at 200 μmol/L.
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Key words:
- natural product /
- Actinomycetospora chlora SNC-032 /
- Thiasporine A /
- analogues /
- synthesis /
- fungicidal activities
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表 1 目标化合物3a~3o和4a~4o对5种植物病原菌的抑菌活性(抑制率/%)
Table 1. Fungicidal activities (inhibition rate/%) of target compounds 3a-3o and 4a-4o against five fungi
化合物
Compd.取代基
R浓度
Concentration/
(μmol/L)水稻纹枯病菌
R. solani油菜菌核病菌
S. sclerotiorum油菜黑胫病菌
L. biglobosa白芨白绢病菌
S. rolfsii烟草黑胫病菌
P. parasitica3a H 200 72.6±0.1 31.4±0.4 47.5±0.1 60.5±0.0 49.2±0.1 100 62.8±0.0 13.3±0.1 9.70±0.2 32.9±0.3 16.2±0.0 3b 2-CH3 200 70.6±0.1 26.2±0.4 39.0±0.1 84.1±0.1 48.5±0.0 100 59.4±0.0 14.6±0.1 18.3±0.1 63.0±0.1 0 3c 2-OCH3 200 62.0±0.0 53.7±0.4 38.9±0.1 65.6±0.1 37.4±0.1 100 41.1±0.1 30.2±0.1 32.6±0.1 28.7±0.4 0 3d 2-CF3 200 73.9±0.0 31.3±0.4 26.9±0.0 94.7±0.0 34.2±0.1 100 55.7±0.1 23.0±0.0 21.8±0.1 82.3±0.1 10.9±0.1 3e 2-OCF3 200 84.5±0.0 57.5±0.2 54.2±0.0 87.9±0.1 63.6±0.1 100 70.0±0.0 34.2±0.1 35.3±0.1 65.7±0.2 25.3±0.2 3f 2-OH 200 50.4±0.1 35.3±0.4 43.1±0.1 20.8±0.1 20.7±0.1 100 55.5±0.1 29.1±0.0 35.2±0.1 20.1±0.3 28.2±0.1 3g 2-F 200 77.3±0.0 81.8±0.2 80.6±0.0 92.9±0.0 70.6±0.0 100 64.7±0.0 56.1±0.1 46.3±0.1 48.0±0.2 59.1±0.1 3h 2-Cl 200 78.0±0.0 55.9±0.3 55.1±0.1 82.0±0.0 54.7±0.1 100 63.1±0.0 41.1±0.1 35.2±0.1 69.3±0.1 19.1±0.1 3i 2-Br 200 84.4±0.0 63.8±0.3 62.3±0.0 92.6±0.1 50.8±0.1 100 68.8±0.0 34.1±0.1 33.4±0.2 76.2±0.1 29.8±0.0 3j 4-CF3 200 63.8±0.0 22.7±0.4 53.2±0.0 50.6±0.0 46.7±0.0 100 50.1±0.0 10.5±0.1 8.10±0.2 25.7±0.3 17.2±0.1 3k 4-OH 200 52.3±0.0 22.4±0.5 49.1±0.0 10.2±0.1 35.5±0.0 100 32.2±0.1 16.7±0.1 19.5±0.2 14.3±0.3 0.50±0.1 3l 4-Cl 200 60.3±0.1 19.7±0.4 45.0±0.0 40.2±0.0 23.0±0.1 100 55.4±0.1 19.5±0.1 18.3±0.2 36.2±0.2 21.9±0.1 3m 4-NH2 200 44.6±0.0 13.3±0.6 16.1±0.1 8.70±0.1 34.4±0.0 100 26.8±0.0 2.30±0.1 8.30±0.2 12.2±0.3 0 3n 3-NH2 200 53.9±0.1 15.1±0.5 5.30±0.0 10.7±0.0 15.7±0.1 100 29.9±0.0 8.30±0.2 10.1±0.1 13.1±0.4 0 3o 2-NH2 200 45.5±0.1 19.9±0.4 16.9±0.1 29.6±0.1 5.9±0.1 100 47.2±0.0 9.60±0.1 12.9±0.2 22.2±0.3 0 4a H 200 43.8±0.0 21.5±0.0 12.2±0.1 84.6±0.1 71.3±0.1 100 38.4±0.1 21.1±0.0 9.00±0.0 41.5±0.3 70.2±0.1 4b 2-CH3 200 26.2±0.0 25.7±0.1 23.0±0.0 100.0±0.0 83.3±0.0 100 32.2±0.1 21.6±0.1 13.3±0.0 40.9±0.3 71.8±0.0 4c 2-OCH3 200 34.7±0.1 36.9±0.0 23.9±0.0 97.9±0.0 77.7±0.0 100 28.0±0.0 28.4±0.1 17.4±0.1 44.1±0.3 54.8±0.3 4d 2-CF3 200 14.1±0.0 14.2±0.0 12.3±0.1 58.3±0.1 35.2±0.2 100 26.7±0.0 14.1±0.1 6.40±0.1 26.0±0.3 27.1±0.0 4e 2-OCF3 200 54.2±0.0 43.5±0.1 38.6±0.0 75.2±0.0 74.6±0.1 100 35.1±0.1 29.2±0.1 28.3±0.1 66.8±0.2 61.7±0.1 4f 2-OH 200 22.8±0.0 21.7±0.0 16.3±0.0 83.0±0.0 58.1±0.3 100 29.0±0.0 24.1±0.1 14.3±0.1 50.3±0.4 54.6±0.0 4g 2-F 200 37.6±0.1 28.0±0.1 15.3±0.1 59.9±0.1 67.1±0.1 100 25.2±0.1 21.3±0.1 10.0±0.1 40.2±0.3 62.1±0.0 4h 2-Cl 200 44.1±0.0 29.7±0.0 21.0±0.1 73.4±0.1 69.1±0.1 100 38.2±0.1 24.2±0.2 15.7±0.1 61.5±0.2 64.1±0.1 4i 2-Br 200 42.0±0.0 22.4±0.0 15.3±0.0 78.3±0.0 69.3±0.0 100 30.9±0.0 21.5±0.1 7.90±0.1 60.1±0.3 52.9±0.0 4j 4-CF3 200 37.1±0.0 37.2±0.0 46.8±0.0 100.0±0.0 74.4±0.0 100 33.6±0.1 25.9±0.2 20.4±0.1 69.4±0.1 63.1±0.0 4k 4-OH 200 10.0±0.1 8.90±0.0 5.30±0.1 0 0 100 28.8±0.1 20.9±0.1 4.80±0.1 1.20±0.5 2.70±0.1 4l 4-Cl 200 38.0±0.1 32.8±0.0 28.6±0.0 71.4±0.0 75.3±0.1 100 34.2±0.0 36.6±0.0 30.4±0.1 90.6±0.1 75.7±0.0 4m 4-NH2 200 15.6±0.1 8.70±0.0 4.40±0.1 0 6.10±0.1 100 31.2±0.0 19.2±0.1 14.3±0.0 0 4.70±0.1 4n 3-NH2 200 47.5±0.1 21.9±0.0 24.7±0.1 4.90±0.0 0 100 54.0±0.1 22.5±0.1 13.7±0.0 11.3±0.5 2.20±0.1 thiasporine A(4o) 2-NH2 200 41.0±0.1 22.3±0.1 15.4±0.1 42.1±0.0 40.1±0.0 100 44.1±0.1 16.5±0.0 10.2±0.1 21.1±0.4 13.2±0.1 噻呋酰胺 thifluzamide 200 95.8±0.1 82.4±0.1 80.9±0.1 100.0±0.0 4.20±0.3 100 94.3±0.0 78.9±0.1 77.6±0.1 100.0±0.0 2.80±0.1 注：每个处理重复3次(平均值±标准差)。Note: Values are the mean ± SD of three replicates. 
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表 2 部分化合物对水稻纹枯病菌、白芨白绢病菌和烟草黑胫病菌的EC50值
Table 2. EC50 of some compounds against R. solani, S. rolfsii and P. parasitica
植物病原菌
Fungi化合物
Compd.取代基
R回归方程
Regression equation相关系数(r)
Correlation cofficientEC50/(μmol/L) 水稻纹枯病菌
R. solani3b 2-CH3 y = 1.0099x + 6.4407 0.9597 37.4±0.2 3d 2-CF3 y = 0.6739x + 5.9595 0.9802 37.7±1.8 3e 2-OCF3 y = 0.8071x + 6.4211 0.9753 17.3±0.7 3h 2-Cl y = 0.7788x + 6.3693 0.9901 17.4±0.6 3i 2-Br y = 0.9425x + 6.5643 0.9893 21.9±0.4 thiasporine A (4o) 2-NH2 y = 0.7138x + 5.6253 0.9908 133.1±2.2 噻呋酰胺 (thifluzamide) y = 0.4128x + 6.5125 0.9943 0.2±0.0 白芨白绢病菌
S. rolfsii3b 2-CH3 y = 1.3917x + 6.8031 0.9892 50.6±2.2 3d 2-CF3 y = 1.8682x + 7.6471 0.9869 38.3±0.2 3e 2-OCF3 y = 1.3353x + 7.0206 0.9983 30.7±2.1 3h 2-Cl y = 1.4759x + 7.2071 0.9927 32.2±1.4 3i 2-Br y = 1.4856x + 7.3205 0.9828 27.4±0.6 4e 2-OCF3 y = 2.3065x + 7.9269 0.8979 53.8±1.7 4h 2-Cl y = 2.6702x + 8.5410 0.9210 47.2±1.3 4i 2-Br y = 2.3683x + 8.2745 0.9466 41.4±2.7 4j 4-CF3 y = 2.1622x + 7.9613 0.9477 42.7±2.6 4l 4-Cl y = 2.5116x + 8.5765 0.9469 37.7±1.2 thiasporine A (4o) 2-NH2 y = 0.7253x + 5.1327 0.9630 656.1±0.9 噻呋酰胺 (thifluzamide) y = 0.8354x + 8.3636 0.9696 0.1±0.0 烟草黑胫病菌
P. parasitica4e 2-OCF3 y = 1.0434x + 6.4496 0.9973 40.8±1.4 4h 2-Cl y = 1.1960x + 6.6059 0.9978 45.4±0.5 4i 2-Br y = 1.5473x + 6.5358 0.9881 101.7±2.9 4j 4-CF3 y = 1.4117x + 6.7695 0.9246 55.8±0.5 4l 4-Cl y = 1.3102x + 7.1177 0.9773 24.2±0.4 thiasporine A(4o) 2-NH2 y = 1.5932x + 5.9353 0.9952 258.8±1.9 噻呋酰胺(thifluzamide) y = 1.6643x + 6.3319 0.9948 158.4±1.6 注：每个处理重复3次(平均值±标准差)。Note: Values are the mean ± SD of three replicates.
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ThiasporineA类似物的设计、合成和抑菌活性_目标化合物的结构鉴定图谱(SupportingInformation).pdf
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