Novel Cyclopropyl-Uracil Derivatives as Potent Herbicides: Design, Synthesis, Activity, and Structure–Activity Relationship

Herbicides are critical for agricultural weed management. Thirty-seven cycloalkyl-substituted pyrimidinedione derivatives were designed and synthesized via molecular hybridization to explore efficient herbicidal leads. All compounds displayed outstanding postemergence activity against broadleaf weeds, and several exhibited favorable activity against grass weeds. Compound 9i surpassed tiafenacil in greenhouse assays, providing 100% control of Zinnia elegans and Abutilon theophrasti at 2.34 g a.i./ha and 90% control of Echinochloa crus-galli at 9.38 g a.i./ha. Its inhibitory activity against protoporphyrinogen oxidase (PPO, IC50 = 9.55 nM) was slightly weaker than tiafenacil (6.85 nM), yet 9i achieved superior in vivo efficacy. Molecular docking analysis suggested that 9i shared a conserved binding mode with tiafenacil and may form an additional hydrogen bond between its cyano group and the Val475 residue of PPO. Density functional theory calculations indicated that its high clogP (4.34) facilitates plant penetration and transmembrane transport, explaining its excellent herbicidal activity independent of stronger PPO inhibition.