N-取代苯基-4-(1-甲基-1H-吡唑-5-基)噻吩-2-甲酰胺的合成、杀菌活性及分子对接

为了寻找结构新颖的琥珀酸脱氢酶 (SDH) 类衍生物，在前期发现吡唑联苯甲酰胺基础上，采用骨架跃迁的策略，设计并合成了18个N-取代苯基-4-(1-甲基-1H-吡唑-5-基) 噻吩-2-甲酰胺类衍生物 ( 3a~3n ， 4a ~ 4d )，其中17个为新化合物。通过 1H NMR、13C NMR 和高分辨质谱 (HRMS) 确证了化合物的结构。离体杀菌活性测试结果表明:部分化合物对小麦赤霉病菌Fusarium graminearum、马铃薯早疫病菌Alternaria solani和草莓灰霉病菌 Botrytis cinerea 显示出较好的杀菌活性，其中化合物 3k 和 4d 对小麦赤霉病菌的EC₅₀值分别为18.5和14.3 mg/L，化合物 4d 对马铃薯早疫病菌的EC₅₀值为15.7 mg/L，活性略高于对照药剂噻呋酰胺 (EC₅₀值27.8 mg/L)，化合物 3k 和 3m 对草莓灰霉病菌的EC₅₀值分别为15.3和 9.9 mg/L，与噻呋酰胺活性 (EC₅₀值10.4 mg/L) 相当。分子对接研究结果显示:具有较高活性的化合物N-(4-氟苯基乙基)-4-(1-甲基-1H-吡唑-5-基) 噻吩-2-甲酰胺 ( 3m ) 与靶酶 (SDH) 的氨基酸残基之间存在较强的氢键作用。

Synthesis,fungicidal activity and molecular docking of N-substitutedphenyl-4-(1-methyl-1H-pyrazol-5-yl)thiophene-2-carboxamide

In order to find novel succinate dehydrogenase inhibitors, based on the previous discovery of the pyrazole-benzoic scaffold, the scaffold hopping strategy was used to design and synthesize 18 N-substitutedphenyl-4-(1-methyl)-1H-pyrazol-5-yl)thiophene-2-carboxamide derivatives ( 3a - 3n , 4a - 4d ), of which 17 are new compounds. Their structures were confirmed by 1H NMR, 13C NMR and HRMS . The fungicidal activity test in vitro showed that some compounds had good activity against Fusarium graminearum, Alternaria solani and Botrytis cinerea. Among them, the EC₅₀ values of compound 3k and 4d against F. graminearum were 18.5 mg/L and 14.3 mg/L, respectively. The EC₅₀ value of compound 4d against A. solani was 15.7 mg/L. It was higher than 27.8 mg/L of thiafluzamide. The EC₅₀ value of compound 3k and 3m against B. cinerea were 15.3 mg/L and 9.9 mg/L, which was equivalent to that of the control agent thiafluzamide (EC₅₀ 10.4 mg/L). The molecular docking study revealed that strong hydrogen bond was formed between the compound N-(4-fluorophenylethyl)-4-(1-methyl-1H-pyrazol-5-yl) thiophene-2-carboxamide ( 3m ) and succinate dehydrogenase (SDH).