PDF(717 KB)
硫乳霉素衍生物的合成、表征和抗真菌评价
Pei Lv, Yiliang Chen, Dawei Wang, Xiangwei Wu, Qing X. Li, Rimao Hua
工程（英文） ›› 2020, Vol. 6 ›› Issue (5) : 560-568.
PDF(717 KB)
PDF(717 KB)
硫乳霉素衍生物的合成、表征和抗真菌评价
Synthesis, Characterization, and Antifungal Evaluation of Thiolactomycin Derivatives
以抑菌活性化合物3-酰基硫代季酮酸为先导，根据3-酰基硫代内酯与蛋白质C171Q KasA的结合模式，设计、合成并表征了一系列5位取代不同的3-酰基硫代季酮酸衍生物。筛选了目标化合物对苹果腐烂病菌（Valsa mali）、新月弯孢菌（Curvularia lunata）、禾谷镰刀菌（Fusarium graminearum）和番茄尖镰孢菌（Fusarium oxysporum f. sp. lycopersici）的抑菌活性。大多数目标化合物在浓度为50 μg·mL–1时对供试菌表现出良好的抑菌活性，其中化合物11c和11i具有最高的广谱抑菌活性。11c和11i对供试菌的有效中浓度（EC50）值分别为1.9~10.7 μg·mL–1和3.1~7.8 μg·mL–1，而嘧菌酯（azoxystrobin）、多菌灵（carbendazim）和氟吡菌酰胺（fluopyram）3种杀真菌剂对苹果腐烂病菌的EC50值分别为0.30、4.22和大于50 μg·mL–1；对新月弯孢菌的EC50值分别为6.7、41.7和0.18 μg·mL–1；对禾谷镰刀菌的EC50值分别为22.4、0.42和0.43 μg·mL–1；对番茄尖镰孢菌的EC50值分别为4.3、0.12和大于50 μg·mL–1。对目标化合物对抗新月弯孢菌的结构及活性进行分析，得到具有统计学意义的比较分子场分析（CoMFA）模型，该模型具有较高预测能力（q2 = 0.9816、r2 = 0.8060），其可靠性得到进一步验证。5位苯亚甲基上的不同取代基对目标化合物活性有显著影响，在苯亚甲基苯环上引入卤素原子可以提高目标化合物对供试菌的活性。
5-Substituted benzylidene 3-acylthiotetronic acids are antifungal. A series of 3-acylthiotetronic acid derivatives with varying substitutions at the 5-position were designed, synthesized, and characterized, based on the binding pose of 3-acyl thiolactone with the protein C171Q KasA. Fungicidal activities of these compounds were screened against Valsa Mali, Curvularia lunata, Fusarium graminearum, and Fusarium oxysporum f. sp. lycopersici. Most target compounds exhibited excellent fungicidal activities against target fungi at the concentration of 50 μg·mL−1. Compounds 11c and 11i displayed the highest activity with a broad spectrum. The median effective concentration (EC50) values of 11c and 11i were 1.9–10.7 and 3.1–7.8 μg·mL−1, respectively, against the tested fungi, while the EC50 values of the fungicides azoxystrobin, carbendazim, and fluopyram were respectively 0.30, 4.22, and > 50 μg·mL−1 against V. Mali; 6.7, 41.7, and 0.18 μg·mL−1 against C. lunata; 22.4, 0.42, and 0.43 μg·mL−1 against F. graminearum; and 4.3, 0.12, and > 50 μg·mL−1 against F. oxysporum f. sp. Lycopersici. The structures and activities of the target compounds against C. lunata were analyzed to obtain a statistically significant comparative molecular field analysis (CoMFA) model with high prediction abilities (q2 = 0.9816, r2 = 0.8060), and its reliability was verified. The different substituents on the benzylidene at the 5-position had significant effects on the activity, while the introduction of a halogen atom at the benzene ring of benzylidene was able to improve the activity against the tested fungi.
3-酰基硫代四酸 / 杀真菌剂 / 定量构效关系 / 抗菌活性
3-Acylthiotetronic acid / Fungicide / Quantitative structure-activity relationship / Antifungal activity
| [1] |
Pennisi E. Armed and dangerous. Science 2010;327(5967):804–5.
|
| [2] |
Anderson PK, Cunningham AA, Patel NG, Morales FJ, Epstein PR, Daszak P. Emerging infectious diseases of plants: pathogen pollution, climate change and agrotechnology drivers. Trends Ecol Evol 2004;19(10):535–44.
|
| [3] |
Fisher MC, Henk DA, Briggs CJ, Brownstein JS, Madoff LC, McCraw SL, et al. Emerging fungal threats to animal, plant and ecosystem health. Nature 2012;484(7393):186–94.
|
| [4] |
Sparks TC, Lorsbach BA. Perspectives on the agrochemical industry and agrochemical discovery. Pest Manag Sci 2017;73(4):672–7.
|
| [5] |
Zhang YJ, Yu JJ, Zhang YN, Zhang X, Cheng CJ, Wang JX, et al. Effect of carbendazim resistance on trichothecene production and aggressiveness of Fusarium graminearum. Mol Plant Microbe Interact 2009;22(9):1143–50.
|
| [6] |
Dijksterhuis J, Van Doorn T, Samson R, Postma J. Effects of seven fungicides on non-target aquatic fungi. Water Air Soil Pollut 2011;222(1–4):421–5.
|
| [7] |
Belgers JDM, Aalderink GH, Van den Brink PJ. Effects of four fungicides on nine non-target submersed macrophytes. Ecotoxicol Environ Saf 2009;72 (2):579–84.
|
| [8] |
Jenni S, Leibundgut M, Maier T, Ban N. Architecture of a fungal fatty acid synthase at 5 Å resolution. Science 2006;311(5765):1263–7.
|
| [9] |
Wakil SJ, Stoops JK, Joshi VC. Fatty acid synthesis and its regulation. Annu Rev Biochem 1983;52(1):537–79.
|
| [10] |
Schweizer E, Hofmann J. Microbial type I fatty acid synthases (FAS): major players in a network of cellular FAS systems. Microbiol Mol Biol Rev 2004;68 (3):501–17.
|
| [11] |
Kremer L, Douglas JD, Baulard AR, Morehouse C, Guy MR, Alland D, et al. Thiolactomycin and related analogues as novel anti-mycobacterial agents targeting KasA and KasB condensing enzymes in Mycobacterium tuberculosis. J Biol Chem 2000;275(22):16857–64.
|
| [12] |
White SW, Zheng J, Zhang YM, Rock CO. The structural biology of type II fatty acid biosynthesis. Annu Rev Biochem 2005;74(1):791–831.
|
| [13] |
Nishida I, Kawaguchi A, Yamada M. Effect of thiolactomycin on the individual enzymes of the fatty acid synthase system in Escherichia coli. J Biochem 1986;99(5):1447–54.
|
| [14] |
Furukawa H, Tsay JT, Jackowski S, Takamura Y, Rock CO. Thiolactomycin resistance in Escherichia coli is associated with the multidrug resistance efflux pump encoded by emrAB. J Bacteriol 1993;175(12):3723–9.
|
| [15] |
Sakya SM, Suarez-Contreras M, Dirlam JP, O’Connell TN, Hayashi SF, Santoro SL, et al. Synthesis and structure–activity relationships of thiotetronic acid analogues of thiolactomycin. Bioorg Med Chem Lett 2001;11(20): 2751–4.
|
| [16] |
Jones AL, Herbert D, Rutter AJ, Dancer JE, Harwood JL. Novel inhibitors of the condensing enzymes of the type II fatty acid synthase of pea (Pisum sativum). Biochem J 2000;347(Pt 1):205–9.
|
| [17] |
Jones SM, Urch JE, Brun R, Harwood JL, Berry C, Gilbert IH. Analogues of thiolactomycin as potential anti-malarial and anti-trypanosomal agents. Bioorg Med Chem 2004;12(4):683–92.
|
| [18] |
Jones SM, Urch JE, Kaiser M, Brun R, Harwood JL, Berry C, et al. Analogues of thiolactomycin as potential antimalarial agents. J Med Chem 2005;48 (19):5932–41.
|
| [19] |
Nayyar A, Jain R. Recent advances in new structural classes of anti-tuberculosis agents. Curr Med Chem 2005;12(16):1873–86.
|
| [20] |
Lv P, Chen Y, Zhao Z, Shi T, Wu X, Xue J, et al. Design, synthesis, and antifungal activities of 3-acyl thiotetronic acid derivatives: new fatty acid synthase inhibitors. J Agric Food Chem 2018;66(4):1023–32.
|
| [21] |
Cherkasov A, Muratov EN, Fourches D, Varnek A, Baskin II, Cronin M, et al. QSAR modeling: where have you been? Where are you going to? J Med Chem 2014;57(12):4977–5010.
|
| [22] |
Wang DW, Lin HY, He B, Wu FX, Chen T, Chen Q, et al. An efficient one-pot synthesis of 2-(aryloxyacetyl)cyclohexane-1,3-diones as herbicidal 4- hydroxyphenylpyruvate dioxygenase inhibitors. J Agric Food Chem 2016;64 (47):8986–93.
|
| [23] |
Wang DW, Lin HY, Cao RJ, Chen T, Wu FX, Hao GF, et al. Synthesis and herbicidal activity of triketone–quinoline hybrids as novel 4- hydroxyphenylpyruvate dioxygenase inhibitors. J Agric Food Chem 2015;63 (23):5587–96.
|
| [24] |
Wang DW, Li Q, Wen K, Ismail I, Liu DD, Niu CW, et al. Synthesis and herbicidal activity of pyrido[2,3-d]pyrimidine-2,4-dione-benzoxazinone hybrids as protoporphyrinogen oxidase inhibitors. J Agric Food Chem 2017;65 (26):5278–86.
|
/
| 〈 |
|
〉 |
