Synthesis and Biological Activity Evaluation of Benzoxazinone-Pyrimidinedione Hybrids as Potent Protoporphyrinogen IX Oxidase Inhibitor

Abstract

Protoporphyrinogen IX oxidase (PPO/Protox, E.C. 1.3.3.4) is recognized as one of the most important targets for herbicide discovery. In this study, we report our ongoing research efforts toward the discovery of novel PPO inhibitors. Specifically, we identified a highly potent new compound series containing a pyrimidinedione moiety and bearing a versatile building blockbenzoxazinone scaffold. Systematic bioassays resulted in the discovery of compound 7af, ethyl 4-( 7 [1,4]oxazin-4-yl)butanoate, which exhibited broad-spectrum and excellent herbicidal activity at the dosage of 37.5 g a.i./ha through postemergence application. The inhibition constant (K i ) value of 7af to Nicotiana tabacum PPO (NtPPO) was 14 nM, while to human PPO (hPPO), it was 44.8 μM, indicating a selective factor of 3200, making it the most selective PPO inhibitor to date. Moreover, molecular simulations further demonstrated the selectivity and the binding mechanism of 7af to NtPPO and hPPO. This study not only identifies a candidate that showed excellent in vivo bioactivity and high safety toward humans but also provides a paradigm for discovering PPO inhibitors with improved performance through molecular simulation and structure-guided optimization.

Discovery of Pyridyl-Benzothiazol Hybrids as Novel Protoporphyrinogen Oxidase Inhibitors via Scaffold Hopping

“…), Abutilon theophrasti (A.T.), and Medicago sativa (M.S.). The evaluations were carried out at concentrations ranging from 18.75 to 150 g ai/ha by using methods that had been previously reported. , Prior to testing, weed seeds were planted in flower pots with an inner diameter of 8 cm and placed within a greenhouse at alternating temperatures of 15 °C (night, 12 h) and 25 °C (day, 12 h) until the third-leaf stage of Digitaria sanguinalis. FLU, SAF, and our compounds were dissolved in DMF and subsequently diluted to the corresponding concentrations using 0.1% Tween-80 before being sprayed onto the weeds.…”

“…According to the reported method, , MD simulations of ligand–protein complexes were carried out using the AMBER 14 software package and the ff14SB force field. The AMBER force fields for the ligands were generated by using the Antechamber program.…”

Design, Synthesis, and Herbicidal Activity of Substituted 3-(Pyridin-2-yl)Phenylamino Derivatives

“…Among the developed herbicides, protoporphyrinogen oxidase inhibitors attract substantial attention due to their favorable environmental safety, low toxicity, low application dosage, and broad spectrum of weed control . For example, several structures such as diphenyl ethers, pyrimidindiones, phenylpyrazoles, pyridazinones, and N -phenyl cyclic amides have been widely and deeply explored for PPO-inhibiting herbicides development. − Protoporphyrinogen oxidase (PPO) promotes the conversion of protoporphyrin IX to protoporphyrinogen IX in the presence of external oxygen. PPO inhibitors could effectively occupy the active cavity of the PPO enzyme and, therefore, significantly reduce its catalytic activity.…”

Synthesis of Benzoxazines by Heterogeneous Multicomponent Biochemo Multienzymes Cascade Reaction

“…Benzoxazines are heterocyclic derivatives , characterized by different biological activities, including neuroprotective, anticancer, and antioxidant properties . They are usually synthesized by harsh and tedious multistep reactions, , the only exception being a limited number of procedures based on heavy metals or, in alternative, electrochemistry . Multienzymes cascade reactions and multicomponent chemistry are considered as a sustainable and green alternatives for the synthesis of heterocyclic derivatives.…”