Natural products are a main source of new chemical entities for use in drug and pesticide discovery. In order to discover lead compounds with high herbicidal activity, a series of new pyrido[2,3-d] pyrimidine derivatives were designed and synthesized using 2-chloronicotinic acid as the starting material. Their structures were characterized with 1H NMR, 13C NMR and HRMS, and the herbicidal activities against dicotyledonous lettuce (Lactuca sativa), field mustard (Brassica campestris), monocotyledonous bentgrass (Agrostis stolonifera) and wheat (Triticum aestivum) were determined. The results indicated that most of the pyrido[2,3-d] pyrimidine derivatives had no marked inhibitory effect on lettuce at 1 mM. However, most of the pyrido[2,3-d] pyrimidine derivatives possessed good activity against bentgrass at 1 mM. Among them, the most active compound, 3-methyl-1-(2,3,4-trifluorophenyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (2o), was as active as the positive controls, the commercial herbicides clomazone and flumioxazin. Molecular simulation was performed with molecular docking and DFT calculations. The docking studies provided strong evidence that 2o acts as an herbicide by inhibition of protoporphyrinogen oxidase. However, the physiological results indicate that it does not act on this target in vivo, implying that it could be metabolically converted to a compound with a different molecular target.

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新型吡啶并[2,3-d]嘧啶化合物的合成、除草活性、作用方式和计算机分析

天然产物是用于药物和农药发现的新化学实体的主要来源。为了发现具有高除草活性的先导化合物，以2-氯烟酸为起始原料，设计合成了一系列新型吡啶并[2,3-d]嘧啶衍生物。通过 1H NMR、13C NMR 和 HRMS 对其结构进行了表征，并测定了其对双子叶生菜 (Lactuca sativa)、芥菜 (Brassica Campestris)、单子叶翦股颖 (Agrostis stolonifera) 和小麦 (Triticum aestivum) 的除草活性。结果表明，大部分吡啶并[2,3-d]嘧啶衍生物在1 mM浓度下对生菜没有明显的抑制作用。然而，大多数吡啶并[2,3-d]嘧啶衍生物在1 mM时对翦股颖具有良好的活性。其中，活性最强的化合物为3-甲基-1-(2,3,4-三氟苯基)吡啶并[2,3-d]嘧啶-2,4(1H,3H)-二酮(2o)。作为阳性对照，商业除草剂异恶草酮和氟啶恶嗪。通过分子对接和DFT计算进行分子模拟。对接研究提供了强有力的证据，证明 2o 通过抑制原卟啉原氧化酶发挥除草剂的作用。然而，生理学结果表明它在体内并不作用于该靶标，这意味着它可以代谢转化为具有不同分子靶标的化合物。