烷氧基取代的嘧啶水杨酸衍生物的设计、合成及生物活性研究

Design,Synthesis and Biological Activity of Pyrimidyl-Salicylate Derivatives Containing Alkoxy Moiety

为寻找新型乙酰羟酸合成酶(EC2.2.1.6,AHAS)抑制剂以克服由靶标突变(P197L突变)所引起的杂草抗性问题,利用"构象柔性度分析"策略设计、合成了一系列烷氧基取代的嘧啶水杨酸衍生物.其中, 9个化合物对P197L突变型AHAS的抗性倍数(RF值)均小于等于1,在酶水平上具有良好的反抗性.特别是2-((4,6-二甲氧基嘧啶-2-基)氧基)-6-(2-氟乙氧基)苯甲酸(5l),被进一步确定为该系列最有效的反抗性AHAS抑制剂(RF=0.31),不仅与氯磺隆(RF=2060)和双草醚(RF=4.57)相比抗性程度大幅降低,并且对野生型At AHAS和P197L突变体的抑制活性均达到了亚微摩尔水平,优于双草醚.此外,在150gai/ha的施用剂量下,2-((4,6-二甲氧基嘧啶-2-基)氧基)-6-(2-(甲氧基)乙氧基)苯甲酸(5a)、2-((4,6-二甲氧基嘧啶-2-基)氧基)-6-(3-(甲氧基)丙氧基)苯甲酸(5f)、2-((4,6-二甲氧基嘧啶-2-基)氧基)-6-(2-氟乙氧基)苯甲酸(5l)和2-((4,6-二甲氧基嘧啶-2-基)氧基)-6-(2,2-二氟乙氧基)苯甲酸(5m)对敏感型和抗性(P197L-AHAS)播娘蒿同时表现出优异的除草活性.值得注意的是,即使在最低剂量37.5 g ai/ha下,化合物5l对这两种杂草的除草防效仍超过85%,表现出良好的活体反抗性,具有深入研究的价值.

In an attempt to search new antiresistance acetohydroxyacid synthase(AHAS, EC 2.2.1.6) inhibitors to combat weed resistance associated with AHAS mutation(P197 L), a series of pyrimidyl-salicylate derivatives containing alkoxy side chain were designed via the strategy of "conformational flexibility analysis" and then synthesized. Nine compounds showed excellent antiresistance property against P197L mutant. Their resistance factor(RF) values ranged from 0.31 to 1.00. Especially, 2-((4,6-dimethoxypyrimidin-2-yl)oxy)-6-(2-fluoroethoxy)benzoic acid(5 l) was further identified as the most promising antiresistance AHAS inhibitor due to quite low RF value(RF=0.31) and sub-micromolar inhibition toward both wild-type At AHAS and P197 L mutant. Furthermore, 2-((4,6-dimethoxypyrimidin-2-yl)oxy)-6-(2-methoxyethoxy)benzoic acid(5 a), 2-((4,6-dimethoxypyrimidin-2-yl)oxy)-6-(3-methoxypropoxy)benzoic acid(5 f), 2-((4,6-dimethoxypyrimidin-2-yl)oxy)-6-(2-fluoroethoxy)benzoic acid(5 l), and 2-(2,2-difluoroethoxy)-6-((4,6-dimethoxypyrimidin-2-yl)oxy)benzoic acid(5 m) also exhibited potent herbicidal activities against sensitive and resistant(P197L-AHAS) Descurainia sophia at 150 g of active ingredient(ai)/ha. Even at the dosage as low as 37.5 g ai/ha, compound 5 l still maintained over 85% weed control toward the above two weeds, which has the great potential to be developed as new lead to control herbicide-resistant weeds caused by P197L mutation.