Design, synthesis, antifungal activities and binding mode with succinate dehydrogenase receptor of quinazolinone oxime ether derivatives
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摘要: 为寻找高活性杀菌化合物,以氟吡菌酰胺为对照,在前期发现的新型硝基甲基喹唑啉酮骨架的基础上,通过中间体衍生化法和活性亚结构拼接等手段,设计、合成了25个未见文献报道的喹唑啉酮肟醚衍生物,所有化合物的结构均通过核磁共振氢谱 (1H NMR)、碳谱 (13C NMR) 及高分辨质谱 (HR-EI-MS) 确证。活体杀菌活性测试表明,目标化合物 A19 和 A25 在500 mg/L下对小麦赤霉病菌Fusarium graminearum的防效分别为43.74%和42.46%,活性远低于氟吡菌酰胺。初步分析,其理化性质以及其与琥珀酸脱氢酶 (SDH) 受体结合模式方面的差异可能是导致这些化合物活性比氟吡菌酰胺低的主要原因。Abstract: In order to discover novel compounds with high fungicidal activities, fluopyram was used as a control, based on the previous discovery of a novel nitromethylquinazolinone skeleton, 25 novel quinazolinone oxime ether derivatives were designed and synthesized by intermediate derivatization and sub-structural combination methods. Their structures were characterized by 1H NMR, 13C NMR and HR-EI-MS spectral data. The preliminary in vivo antifungal evaluation results showed that compounds A19 and A25 were 43.74% and 42.46% control Fusarium graminearum at a concentration of 500 mg/L, respectively. However, the antifungal activities were much lower than that of fluopyram. The differences in physicochemical properties and binding mode with succinate dehydrogenase (SDH) receptor between these compounds and fluopyram may be the major factor which reduced the antifungal activities.
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表 1 关键中间体7的合成条件筛选
Table 1. Screening of synthetic conditions for key intermediate 7
编号
Number反应试剂
Reagents温度
Temperature/℃溶剂
Solvent收率
Yield/%1 Mg(ClO4)2/i-Pr2NEt r.t. CH3CN 80 2 Mg(ClO4)2/Et3N r.t.~80 CH3CN - 3 LiBF4/i-Pr2NEt r.t. CH3CN 75 4 CS2/TBD 0~r.t. DCM 75 5 NaNO2 r.t. DMSO/H2O 68 6 n-BuLi/Me3SiSiMe3 0~ r.t. THF 71 7 SnCl2 r.t. THF 85 8 SnCl2 r.t. EtOH 80 9 SnCl2 r.t. DCM 54 10 AlCl3 r.t. THF 50 表 2 目标化合物的理化性质以及活体杀菌活性
Table 2. The physiochemical properties and in vivo antifungal activities of target compounds
化合物
Compd.理化性质
Physiochemical properties防治效果
Control efficacy/%
(500 mg/L)logP logS pKa TPSA/Å2 小麦赤霉病菌
Fusarium graminearumA1 1.65 −2.87 1.22 63.05 14.46 A2 1.14 −2.59 1.22 63.05 11.11 A3 2.48 −3.65 1.22 63.05 17.97 A4 1.65 −3.21 1.22 63.05 16.67 A5 1.00 −3.58 1.22 63.05 23.70 A6 0.95 −3.72 1.22 63.05 31.85 A7 1.93 −3.71 1.22 63.05 8.89 A8 2.53 −4.25 1.22 63.05 24.65 A9 2.18 −4.01 1.22 72.28 32.59 A10 2.52 −4.24 1.22 63.05 22.22 A11 2.53 −4.25 1.22 63.05 32.56 A12 2.23 −4.35 1.22 63.05 −5.37 A13 2.35 −4.32 1.22 63.05 8.15 A14 2.36 −4.39 1.22 63.05 32.59 A15 2.78 −4.79 1.22 63.05 34.07 A16 2.90 −4.41 1.22 63.05 12.59 A17 2.89 −4.42 1.22 63.05 −6.67 A18 3.06 −4.66 1.22 63.05 15.56 A19 3.51 −4.94 1.22 63.05 43.74 A20 4.00 −5.23 1.22 63.05 12.59 A21 2.87 −4.50 1.22 63.05 −2.96 A22 3.30 −4.93 1.22 63.05 37.78 A23 2.29 −4.21 1.22 63.05 12.59 A24 3.27 −5.11 1.22 63.05 12.59 A25 2.20 −3.87 1.33 75.94 42.46 氟吡菌酰胺 fluopyram 3.87 −5.13 1.72 41.99 100.00 CK — — — — 0.00 -
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