Design, synthesis, SAR and molecular docking of novel green niacin-triketone HPPD inhibitor

4-Hydroxyphenylpyruvate dioxygenase (EC 1.13.11.27, HPPD) is a very important target for the discovery of novel bleaching herbicides. In order to discover novel triketone green HPPD inhibitors with excellent herbicidal activity and crop selectivity, the natural product leptospermone was selected as the template compound, and niacin was employed as bioisostere to design and synthesize a series of novel substituted niacin-triketone derivatives. Some of the target compounds showed potent Arabidopsis thaliana HPPD (AtHPPD) inhibitory activity in vitro. Especially compound II-1 displayed the best herbicidal activity (IC50 = 0.262 mu M, AtHPPD), and was safe for Zea mays at concentration of 300 g ai/ha. Molecular docking results indicated that the triketone moiety of compound II-1 could form a bidentate complex with Fe(II), and the pyridine subunit interacted with Phe430 and Phe360 via pi-pi packing. The present work indicated that 3-hydroxy-2-nicotinoylcyclohex-2-en-1-one could be a potential lead structure for developing novel green HPPD inhibitors.