Design and synthesis of flavokawain-derived pyrimidines as potential herbicides: Biological evaluation and molecular docking studies.

Growing environmental and human health concerns have intensified the search for safer herbicides derived from natural products and their semisynthetic analogues. Herein, a series of 26 pyrimidine derivatives bearing electron-donating, electron-withdrawing, and heterocyclic substituents were synthesized from flavokawains and related analogues and evaluated for herbicidal activity against Chinese amaranth (Amaranthus tricolor) and barnyard grass (Echinochloa crus-galli). Structure-activity relationship analysis revealed that both the type and position of the substituents markedly influenced herbicidal activity, with ortho-substituted derivatives generally exhibiting the strongest inhibition of seedling growth. Among the synthesized compounds, the 2-hydroxypyrimidine derivative 15 exhibited the highest herbicidal activity. At 1600 μM, compound 15 inhibited the shoot and root growth of E. crus-galli by 81 ± 3.49% and 86 ± 4.54%, respectively, with IC₅₀ values of 0.41 mM for both growth parameters, while showing a comparatively moderate effect on seed germination. Mechanistic studies demonstrated that compound 15 reduced seed imbibition, inhibited α-amylase activity, and decreased photosynthetic pigment contents. Molecular docking analysis suggested that the hydroxy group, aromatic ring, and pyrimidine moiety may play important roles in the binding of the compounds to the α-amylase active site. These interactions may contribute to the observed α-amylase inhibitory activity. These findings identify flavokawain-derived pyrimidines as promising lead scaffolds for the development of herbicides based on natural product-inspired structures.