Cyclopropyl-enhanced bioavailability, not target-site potency, drives the herbicidal activity of FM-1688, a novel PPO...

The persistent challenge of weed competition in agriculture necessitates the development of novel herbicides with enhanced efficacy and improved physicochemical properties. This study employed a molecular hybridization strategy to optimize tiafenacil by incorporating cyclopropyl and cyclobutyl moieties into pyrimidinedione scaffolds, aiming to discover more effective protoporphyrinogen oxidase (PPO)-inhibiting herbicides.

Thirty-four novel pyrimidinedione derivatives were synthesized and evaluated for post-emergence herbicidal activity. Structure-activity relationship (SAR) analysis revealed that cyclopropyl derivatives consistently outperformed cyclobutyl analogs, with methyl esters providing optimal activity. In the greenhouse assay, compound FM-1688 (6aa) demonstrated exceptional in vivo herbicidal efficacy, achieving 100% control of broadleaf weeds (Zinnia elegans and Abutilon theophrasti) at 2.34375 g active ingredient (a.i.)/ha and 80% control of grass weeds (Echinochloa crus-galli) at 9.375 g a.i./ha, significantly surpassing the commercial standard tiafenacil (which achieved only 40% control of E. crus-galli at the same rate). Crucially, enzymatic inhibition experiments revealed that FM-1688 (half-maximal inhibitory concentration (IC₅₀) = 5.95 nm) possesses only minimally greater in vitro target-site potency than tiafenacil (IC₅₀ = 6.85 nm). This major discrepancy between in vivo efficacy and in vitro potency suggests the 'cyclopropyl-enhanced activity' is not a target-site (pharmacodynamic) effect. Molecular modeling supported this; docking studies revealed nearly identical binding poses and comparable binding energies (-8.6 kcal/mol for FM-1688 versus -8.7 kcal/mol for tiafenacil). Instead, density functional theory (DFT) calculations identified the true driver: FM-1688 possesses a significantly reduced molecular dipole moment (3.19 D) compared to tiafenacil (5.89 D), suggesting its superior greenhouse efficacy is driven by enhanced bioavailability and membrane permeability.

The cyclopropyl-containing pyrimidinedione derivative FM-1688 represents a highly promising herbicide candidate. Its superior in vivo activity appears to be driven by cyclopropyl-enhanced pharmacokinetic properties (bioavailability) rather than enhanced target-site binding. This finding provides a new rationale for agrochemical design, warranting further development for sustainable weed management. © 2025 Society of Chemical Industry.