新型2,4,6-三取代嘧啶衍生物作为琥铂酸脱氢酶抑制剂的研究

Discovery of Novel 2,4,6-Trisubstituted Pyrimidine Derivatives as Succinate Dehydrogenase Inhibitors

设计并合成了36个未见文献报道的嘧啶类衍生物,并用IR、1HNMR、13CNMR和HRMS对其结构进行了表征.以5种植物病原真菌即水稻纹枯、小麦赤霉、玉米小斑、油菜菌核和番茄灰霉病菌为靶标,对合成化合物的抑菌活性进行了测定.结果显示,在20 mg/L时,其中的大多数都有着显著的抑菌活性.其中,化合物2-甲基-4-(呋喃-2-基)-6-(对甲苯基)嘧啶(2c)和2-(1-吡唑-1-基)-4-(4-氯苯基)-6-(5-甲基呋喃-2-基)嘧啶(3d)对油菜菌核的抑制活性最强,其EC50值分别为0.072、0.077 mg/L,与市售杀菌剂氟吡菌酰胺(EC50=0.244 mg/L)相比,具有更好的抑菌活性.与此同时,还测定了化合物2c和3d对琥珀酸脱氢酶(SDH)的抑制活性.结果表明,它们的半数抑制浓度(IC50)分别为0.115和0.121mg/L,也比氟吡菌酰胺(IC50=0.356 mg/L)有更好的抑制活性.分子对接研究结果显示,化合物2c、3d和氟吡菌酰胺与SDH的结合能分别为-32.2,-31.8和-28.9 kJ/mol,这表明它们对SDH的亲和力比氟吡菌酰胺更强.化合物2c和3d对SDH的抑制活性尚属首次报道.

Thirty-six unreported pyrimidine analogues were designed,synthesized and characterized by IR,1 H NMR,13 C NMR and HRMS.Their antifungal activities were determined against five plant pathogenic fungi namely Rhizoctonia solani,Fusarum graminearum,Helminthosporium maydis,Sclerotinia sclerotiorum and Botrytis cinerea.The results indicated that most of them revealed significant antifungal activities at 20 mg/L.Among them,4-(furan-2-yl)-2-methyl-6-(p-tolyl)pyrimidine(2 c)and 4-(4-chlorophenyl)-6-(5-methylfuran-2-yl)-2-(1 H-pyrazol-1-yl)pyrimidine(3 d)showed the strongest activities against Sclerotinia sclerotiorum and their median effect concentrations(EC50)were 0.072 and 0.077 mg/L,respectively,which implied that they had better antifungal activities than the commercial fungicide fluopyram(EC50=0.244 mg/L).Meanwhile,the inhibitory activities of compounds 2 c and 3 d were determined against succinate dehydrogenase(SDH).The results exhibited that their half inhibitory concentrations(IC50)were 0.115 and 0.121 mg/L,respectively,indicating that they also had better inhibitory activities than fluopyram(IC50=0.356 mg/L).Molecular docking studies demonstrated that the binding energy of compounds 2 c,3 d and fluopyram to SDH was-32.2 kJ/mol,-31.8 kJ/mol and-28.9 k J/mol,respectively,which represented that they had stronger affinities than fluopyram.The inhibitory activities of compounds 2 c and 3 d against SDH have been reported for the first time.