Design, synthesis, herbicidal activity and CoMFA of aryl-formyl piperidinone HPPD inhibitors.

Isoxazole, nicotinic acid and benzoic acid are important components in many natural products and useful synthons to build macrostructures having valuable biological activities. In continuation of our effort to discover 4-hydroxyphenylpyruvate dioxygenase (HPPD, EC 1.13.11.27) inhibitors and search for active fragments from natural products, a series of substituted aryl-formyl piperidinone derivatives with natural product fragments was rationally designed, synthesized and tested for their herbicidal activity. Compound I-9 was considered the most effective candidate with an IC50 value of 0.260 µM. The molecular docking results showed that the triketone group of compound I-9 forms a bidentate complex with a metal ion, and the benzene ring interacted with Phe424 and Phe381 via π-π stacking, which was similar to the mechanisms of mesotrione. The present work indicates that compound I-9 may serve as a potential lead compound for further development of green HPPD inhibitors.

Fragment splicing-based design, synthesis and safener activity of novel substituted phenyl oxazole derivatives.

Fragment splicing is a primary strategy in the design and optimization of leading compound toward new skeleton with target bioactivity. Herein a series of novel substituted phenyl oxazole derivatives were designed via fragment analysis and coupling strategy that led to highly potent and bio-selective herbicide safener. The biological tests showed that most of the compounds could enhance the maize growth index, glutathione content and anti-reverse enzyme glutathione S-transferase activity in vivo. The molecular docking model exhibited that the novel compound could compete with chlorsulfuron binding to the herbicide target enzyme, which consequently attained the herbicide detoxification. Especially compound I-f displayed the best activities than commercial safener isoxadifen-ethyl and other compounds. The present work demonstrates that the synthesized compounds could be developed as potential candidates for the discovery of novel herbicide safeners in the future.

Discovery of N-Aroyl Diketone/Triketone Derivatives as Novel 4-Hydroxyphenylpyruvate Dioxygenase Inhibiting-Based Herbicides.

4-Hydroxyphenylpyruvate dioxygenase (HPPD, EC 1.13.11.27) is an important target site for discovering new bleaching herbicides. To explore novel HPPD inhibitors with excellent herbicidal activity, a series of novel N-aroyl diketone/triketone derivatives were rationally designed by splicing active groups and bioisosterism. Bioassays revealed that most of these derivatives displayed preferable herbicidal activity against Echinochloa crus-galli (EC) at 0.045 mmol/m2 and Abutilon juncea (AJ) at 0.090 mmol/m2. In particular, compound I-f was more potent compared to the commercialized compound mesotrione. Molecular docking indicated that the corresponding active molecules of target compounds and mesotrione shared similar interplay with surrounding residues, which led to a perfect interaction with the active site of Arabidopsis thaliana HPPD.