[01] Yulin Zhou, School of Pharmaceutical Engineering and Life Sciences, Changzhou University, Changzhou, P. R. China. [02] Xiangjian Xu, School of Pharmaceutical Engineering and Life Sciences, Changzhou University, Changzhou, P. R. China. [03] Bin Wang, School of Pharmaceutical Engineering and Life Sciences, Changzhou University, Changzhou, P. R. China. [04] Lele Zhang, School of Pharmaceutical Engineering and Life Sciences, Changzhou University, Changzhou, P. R. China. [05] Hang Hu, School of Pharmaceutical Engineering and Life Sciences, Changzhou University, Changzhou, P. R. China. [06] Defeng Xu, School of Pharmaceutical Engineering and Life Sciences, Changzhou University, Changzhou, P. R. China; National & Local Joint Engineering Research Center for High-efficiency Refining and High-quality Utilization of Biomass, Changzhou University, Changzhou, P. R. China.

A series of new pyrimidinylthiosalicylic acid derivatives, (4, 6-dimethoxypyrimidin-2-yl) thiosalicylate aldoxime esters (6a-6x), were designed and synthesized as potential herbicidal acetolactate synthase (ALS) inhibitors. All synthesized new compounds were characterized by ¹H NMR, ¹³C NMR, and high resolution mass spectrometry (HRMS). The herbicidal activity and in vitro ALS enzyme inhibition activity studies were performed to test the synthesized new compounds. The herbicidal activity study shows that all synthesized new compounds exhibit no herbicidal activity against Setaria viridis and Eleusine indica and no harm to rice. Among the tested compounds, 6d, 6i, 6j, 6n, 6o, and 6p exhibit potent herbicidal activity (inhibitory ratio over 85%) against barnyard grass at 10 mg/L, which are better than other synthesized new compounds and Pyriftalid. 6d, 6i, 6j, 6n, 6o, and 6p also exhibit efficient inhibitory activity (IC₅₀ 2.63-8.02 mM) against E.coli ALS enzyme in in vitro ALS enzyme inhibition activity study. The structure-activity relationship (SAR) analysis reveals that benzaldoxime ester is a highly efficient substituent group for ALS inhibitors, which is better than heteroaromatic aldoxime esters and aliphatic aldoxime ester, and the introduction of -OBoc (6n, 6o), -NH₂ (6p), or -F (6d, 6i, 6j) to the benzaldoxime ester can further enhance ALS enzyme inhibition activity. Molecular docking simulation was performed to gain a better understanding of the probable binding modes of these compounds. Compounds 6d, 6i, 6j, 6n, 6o, and 6p reported in the present work may serve as new candidates for herbicidal ALS inhibitors.

Pyrimidylsalicylates, Acetolactate Synthase Inhibitors, Aldoxime Esters, Herbicidal Activity, Molecular Docking Simulation

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