Synthesis, Herbicidal Activity, Mode of Action, and In Silico Analysis of Novel Pyrido[2,3-]pyrimidine Compounds.

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-] pyrimidine derivatives were designed and synthesized using 2-chloronicotinic acid as the starting material. Their structures were characterized with H NMR, C NMR and HRMS, and the herbicidal activities against dicotyledonous lettuce (), field mustard (), monocotyledonous bentgrass () and wheat () were determined. The results indicated that most of the pyrido[2,3-] pyrimidine derivatives had no marked inhibitory effect on lettuce at 1 mM. However, most of the pyrido[2,3-] 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-]pyrimidine-2,4(1,3)-dione (), 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 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.