Synthesis of Novel Propionamide-Methylpyrazole Carboxylates as Herbicidal Candidates.

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