<i>β</i> ‐Substitution and prodrug derivation leading to identification of fosmidomycin analogs with improved herbicidal activity

BACKGROUND: The rapid evolution and spread of herbicide resistance poses a great challenge to the sustainability of modern agriculture and finding new herbicides based on novel modes of action (MOA) has become an urgent need. The enzyme 1-deoxy-d-xylulose-5-phosphate reductoisomerase (DXR) in the 2-C-methyl-d-erythritol 4-phosphate (MEP) pathway is considered an ideal novel target for developing new herbicides and therefore its natural inhibitor fosmidomycin (FOS) is an excellent starting point from which to design new herbicidal candidates. RESULTS: This work presents the design and synthesis of a series of β-substituted FOS analogs 10a-m and 11a-m and a prodrug 15i, the diethyl ester of 11i, for evaluating their herbicidal activity. Most compounds exhibited high inhibition activity toward the DXR enzyme in the MEP pathway, and 11i and 11l were among the most active, with half-maximal inhibitory concentrations of 0.24 and 0.27 μm, respectively. In pre- and post-emergence tests on model plants, ten compounds had higher activities than FOS, and 15i achieved more than tenfold pre-emergence and twofold post-emergence activity against the test weeds. The MEP pathway rescue of Arabidopsis inhibited by 11i as a representative had a higher rescue rate than that by FOS, while molecular docking revealed binding enhancement in the DXR active site due to β-substitution, suggesting that β-substituted FOS analogs may be herbicidally active by targeting DXR, like the MOA of FOS. CONCLUSION: The combination of β-substitution with prodrug derivation to modify the lead structure FOS is an effective strategy for developing herbicide-active FOS analogs. © 2026 Society of Chemical Industry.