Pharmacophore Recombination Design, Synthesis, and Bioactivity of Ester-Substituted Pyrazole Purine Derivatives as Herbicide Safeners

Mesosulfuron-methyl, an acetolactate synthase (ALS) inhibitor primarily applied to wheat and rye, can injure or even kill wheat crops. Herbicide safeners can improve the herbicide resistance of crops without reducing the herbicidal effect on targeted weed species. Herein, we present a series of pyrazole purine derivatives with the primary structure of the natural product cytokinin and commercialized safener mefenpyridyl, designed using the pharmacophore recombination method. The title compounds were synthesized and characterized using infrared spectroscopy, ¹H and ¹³C nuclear magnetic resonance spectroscopy, and high-resolution mass spectrometry. A bioactivity assay proved that most of the target compounds can reduce the wheat phytotoxicity of mesosulfuron-methyl. Measurements of chlorophyll and glutathione contents, along with other enzyme activity assays, confirmed that compounds <b>I-15</b> and <b>I-13</b> exhibit higher safety activities compared with the mefenpyr-diethyl safener. Molecular structure comparisons demonstrated that <b>I-15</b> is more readily absorbed and disseminated through the crop than the commercialized safener mefenpyr-diethyl. Molecular docking models and molecular dynamics simulations elucidated the protective mechanism of safeners; specifically, compound <b>I-15</b> competitively binds to the ALS active site with mesosulfuron-methyl. The current study reveals the potential of pyrazole purine derivatives in the future discovery of novel herbicide safeners.