Synthesis of Novel\nPropionamide-Methylpyrazole Carboxylates\nas Herbicidal Candidates

Transketolase (TKL; EC 2.2.1.1) is a highly promising\npotential\ntarget for herbicidal applications. To identify novel TKL inhibitors,\nwe designed and synthesized a series of 3-oxopropionamide-1-methylpyrazole\ncarboxylate analogues and assessed their herbicidal activities. Ethyl\n3-((1-((2,4-dichlorophenyl)amino)-1-oxopropan-2-yl)oxy)-1-methyl-1<i>H</i>-pyrazole-5-carboxylate (<b>D15</b>) and ethyl 1-methyl-3-((1-oxo-1-((thiophen-2-ylmethyl)amino)propan-2-yl)oxy)-1<i>H</i>-pyrazole-5-carboxylate (<b>D20</b>) exhibited superior\ngrowth inhibition activities against both the root and stem of Amaranthus retroflexus (A. retroflexus) compared to nicosulfuron and mesotrione. Additionally, <b>D15</b> achieved an inhibition rate of more than 90% against the roots and\nstems of Digitaria sanguinalis (D. sanguinalis), outperforming the four control agents\nat a concentration of 200 mg/L using the small cup method. In the\npre-emergence herbicidal activity test, <b>D15</b> effectively\ninhibited D. sanguinalis by more than\n90% at 150 g ai/ha, surpassing the efficacy of the control, mesotrione.\nConversely, in the postemergence herbicidal activity test, <b>D20</b> exhibited efficient inhibition of A. retroflexus by more than 90% at 150 g ai/ha, outperforming the control agents\nnicosulfuron, mesotrione, and metamifop. The results of the TKL enzyme\nactivity test showed that the IC<sub>50</sub> values of compounds <b>D15</b> and <b>D20</b> were 0.384 and 0.655 mg/L, respectively,\nwhich were close to those of the control agents. Furthermore, molecular\ndocking and molecular dynamics simulation studies revealed that <b>D15</b> and <b>D20</b> interacted favorably with the TKL\nof Setaria viridis. Such findings highlight\nthe promising potential of <b>D15</b> and <b>D20</b> as\nlead TKL inhibitors for the optimization of new herbicides.