Design, synthesis, and biological evaluation of oxime ether derivatives containing 1,5-dimethyl-6-thioxo-1,3,5-triazinane-2,4-dione as protoporphyrinogen IX oxidase inhibitors

Abstract

BACKGROUND

Herbicides based on protoporphyrinogen IX oxidase (PPO; EC 1.3.3.4) are widely used for weeding control in agricultural fields to safeguard food security. PPO herbicides, because of their low dosage, rapid action on weeds, slow accumulation in the environment and low toxicity to mammals, have become an important field of research in the development of new herbicides. This study presents a novel molecular scaffold with remarkably potent herbicidal activity.

RESULTS

A series of novel oxime ether derivatives containing 1,5-dimethyl-6-thioxo-1,3,5-triazinane-2,4-dione 6a–6z were designed and synthesized based on bioisosterism and substructure splicing, and characterized by ¹H and ¹³C nuclear magnetic resonance spectroscopies, and high-resolution mass spectrometry. The configuration of compound 6u was confirmed by single-crystal X-ray diffraction. Compound 6r displayed excellent herbicidal activity of >95% against Echinochloa crus-galli, Digitaria sanguinalis, Medicago sativa and Conyza canadensis at a dosage of 37.5 g hm–2 in the glasshouse. At a dosage of 75 g hm–2, 6r was safe for application on rice and showed low toxicity (>200 μg g–1) towards Apis mellifera. Transcriptomics analysis of E. crus-galli treated by compound 6r, using oxadiazon as a positive control, revealed the compound's mode-of-action. There were eight metabolic and biosynthetic pathways of DEGs containing ‘photosynthesis’, ‘porphyrin metabolism’, ‘carotenoid biosynthesis’ and so on between 6r and oxadiazon as same. Scaffold94.443 (coproporphyrinogen-III oxidase) as upstream protoporphyrinogen IX changes were downregulated with quantitative reverse transcription PCR combined analysis treated 6r and oxadiazon in chlorophyll biosynthesis. Compound 6r target may be PPO and the NtPPO inhibitory effects, as represented by Ki, was 30.34 nm in vitro. Molecular docking showed that 6r could form two hydrogen bonds with Arg98.

CONCLUSION

Through bioisosterism and substructure splicing, we successfully developed compound 6r as lead compound exhibiting herbicidal activity, with no harm to rice and honeybees. Further development of herbicides based on this scaffold is warranted. © 2025 Society of Chemical Industry.