Discovery of a Potent Thieno[2,3-d]pyrimidine-2,4-dione-Based Protoporphyrinogen IX Oxidase Inhibitor through an In Silico Structure-Guided Optimization Approach

Abstract

A key objective for herbicide research is to develop new compounds with improved bioactivity. Protoporphyrinogen IX oxidase (PPO) is an essential target for herbicide discovery. Here, we report using an in silico structure-guided optimization approach of our previous lead compound 1 and designed and synthesized a new series of compounds 2−6. Systematic bioassays led to the discovery of a highly potent compound 6g,)-dione, which exhibited an excellent and wide spectrum of weed control at the rates of 30−75 g ai/ha by the postemergence application and is relatively safe on maize at 75 g ai/ha. Additionally, the K i value of 6g to Nicotiana tabacum PPO (NtPPO) was found to be 2.5 nM, showing 3-, 12-, and 18-fold higher potency relative to compound 1 (K i = 7.4 nM), trifludimoxazin (K i = 31 nM), and flumioxazin (K i = 46 nM), respectively. Furthermore, molecular simulations further suggested that the thieno[2,3-d]pyrimidine-2,4-dione moiety of 6g could form a more favorable π−π stacking interaction with the Phe392 of NtPPO than the heterocyclic moiety of compound 1. This study provides an effective strategy to obtain enzyme inhibitors with improved performance through molecular simulation and structure-guided optimization.

Design, Synthesis, and Metabolism Studies of N-1,4-Diketophenyltriazinones as Protoporphyrinogen IX Oxidase Inhibitors

“…The MD simulations of Ic -, IIc -, and IIIc -NtPPO systems are performed with AMBER 14 software. The methods for MD are shown in the Supporting Information and referred to our previous reports. , Briefly, the parameters for ligands used for MD are generated using the Antechamber program. The parameters for MD of the ligand–receptor systems are generated using the tleap module.…”

Synthesis of Novel α-Trifluoroanisole Derivatives Containing Phenylpyridine Moieties with Herbicidal Activity

“…Nt PPO was prepared as reported previously [ 35 ]. The inhibitory activities of the Nt PPO enzyme were determined using a previously reported method [ 36 ]. The Nt PPO catalytic rate was calculated by measuring changes in the concentrations of the Nt PPO catalytic product protoporphyrin IX over a given time period by measuring the absorbance at 410 nm via a UV–Vis spectrophotometer.…”

A Competitive Edge: Competitor Inspired Scaffold Hopping in Herbicide Lead Optimization

“…Compound 18 was shown to have very good post- and pre-emergence herbicidal efficacy that is comparable to the commercial PPO inhibitor flumioxazin. Very recently, Wang and Xi expanded their scaffold hopping efforts on PPO herbicides by replacing the pyridine ring of compound 18 with a thiophene heterocycle, thus affording thieno-uracil derivative 19 , which exhibits broad-spectrum efficacy with an interesting maize safety profile . Xi and co-workers built further on the idea of bicyclic heterocycle systems by replacing the heteroaromatic rings of compounds 18 and 19 with an alkane ring, such as that represented by compound 20 .…”

“…Very recently, Wang and Xi expanded their scaffold hopping efforts on PPO herbicides by replacing the pyridine ring of compound 18 with a thiophene heterocycle, thus affording thieno-uracil derivative 19, which exhibits broad-spectrum efficacy with an interesting maize safety profile. 17 Xi and coworkers built further on the idea of bicyclic heterocycle systems by replacing the heteroaromatic rings of compounds 18 and 19 with an alkane ring, such as that represented by compound 20. 18 Not only was compound 20 shown to be a broad-spectrum herbicide at dosages as low as 37.5 g/ha, but it also exhibited improved wheat selectivity in post-emergence application compared to the commercial PPO inhibitors flumioxazine and trifludimoxazin (9).…”