Discovery of N-Phenylaminomethylthioacetylpyrimidine-2,4-diones as Protoporphyrinogen IX Oxidase Inhibitors through a Reaction Intermediate Derivation Approach

Protoporphyrinogen oxidase (PPO, EC 1.3.3.4) is an effective target for green herbicide discovery. In this work, we reported the unexpected discovery of a novel series of N-phenylaminomethylthioacetylpyrimidine-2,4-diones (2–6) as promising PPO inhibitors based on investigating the reaction intermediates of our initially designed N-phenyluracil thiazolidinone (1). An efficient one-pot procedure that gave 41 target compounds in good to high yields was developed. Systematic Nicotiana tabacum PPO (NtPPO) inhibitory and herbicidal activity evaluations led to identifying some compounds with improved NtPPO inhibition potency than saflufenacil and good post-emergence herbicidal activity at 37.5–150 g of ai/ha. Among these analogues, ethyl 2-((((2-chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-(trifluoromethyl)-3,6-dihydropyrimidin-1(2H)-yl)phenyl)amino)methyl)thio)acetate (2c) (Ki = 11 nM), exhibited excellent weed control at 37.5–150 g of ai/ha and was safe for rice at 150 g of ai/ha, indicating that compound 2c has the potential to be developed as a new herbicide for weed management in paddy fields. Additionally, our molecular simulation and metabolism studies showed that the side chains of compound 2c could form a hydrogen-bond-mediated seven-membered ring system; substituting a methyl group at R1 could reinforce the hydrogen bond of the ring system and reduce the metabolic rate of target compounds in planta.