Computer-Assisted Proposition of Promising Aryloxyacetic Acid Derivatives as HPPD Inhibitors

Abstract

A series of aryloxyacetic acid derivatives have demonstrated promising herbicidal performance by inhibition of the hydroxyphenylpyruvate deoxygenase (HPPD) enzyme. We hereby applied quantitative structure−activity relationship (QSAR) and docking strategies to model and chemically understand the bioactivities of these compounds and subsequently propose unprecedented analogues aiming at improving the herbicidal and environmental properties. Bulky halogens at the 2-, 3-, 4-, and 6positions of an aromatic ring, CF 3 in 4-position, and the 2-NO 2 group in a phenyl ring appear to favor the HPPD inhibition. At the same time, Me and OMe substituents contribute to decreasing the pK i values. Accordingly, a few compounds were proposed and the candidate with 2,4,6-triBr substituents demonstrated an estimated pK i similar to those of the best library compounds. This finding was corroborated by the docking scores of the ligand−enzyme interactions. In addition, the high calculated lipophilicity of some proposed agrochemicals suggests that they should have low soil mobility and, therefore, are not prone to easily leach out and reach groundwater, despite causing other ecological issues.

Discovery of Novel Pyrazole Derivatives with Improved Crop Safety as 4-Hydroxyphenylpyruvate Dioxygenase-Targeted Herbicides

“…Weeds compete with crop seedlings for sunlight, space, water, and nutrients, hindering the normal growth of crops and resulting in crop yield loss . The management and disposal of weeds are critical steps in maintaining agricultural production. , The use of herbicides can effectively enhance crop production; however, the extensive use of traditional herbicides has resulted in substantial environment damage and an increase in herbicide-resistant plants, presenting an opportunity for developing new herbicides. − Therefore, there is an urgent need for agricultural producers to develop new, effective, and low-risk herbicides. , 4-Hydroxyphenylpyruvate dioxygenase (HPPD) is one of the most important herbicide targets; HPPD-targeted herbicides cause abnormal photosynthesis by inhibiting the HPPD, following the unique bleaching symptom and eventually resulting in the death of weeds, and thus, HPPD-targeted herbicides have become a global research hot spot. − HPPD-targeted herbicides are broadly classified into three categories, including triketones, isoxazoles, and pyrazoles. Most commercial herbicides belong to the class of pyrazoles and triketones…”

Fluorinated benzoxazinones designed via MIA‐QSAR, docking and molecular dynamics as protoporphyrinogen IX oxidase inhibitors

“…Lipophilicity is another parameter widely used to describe bioactivity as a result of cell permeation and leaf uptake, and lipophilicity is usually described as the octanol–water partition coefficient (log P ) 1 . High lipophilic compounds are less mobile within soil rich in organic matter, which reduces runoff and leaching, despite some issues related to bioaccumulation 39 . According to the log P calculated through the Molinspiration (https://molinspiration.com) platform, the best PPO inhibitor candidates P3 and P6 should exhibit greater lipophilicity than that of most active compounds within the series of benzoxazinones (Fig.…”

Carboxylic Acid Derivatives in Herbicide Development

“…Recently, CADD has emerged as one of the significant tools for the discovery of novel and efficient pesticides and has also been successfully used in the search for HPPD inhibitory herbicides. For instance, the structure of compound 54 has been found as a potential HPPD inhibitor via the CADD method and is further supported by quantitative structure–activity relationship (QSAR) and docking studies …”

“…For instance, the structure of compound 54 has been found as a potential HPPD inhibitor via the CADD method and is further supported by quantitative structure− activity relationship (QSAR) and docking studies. 102 Although significant progress has been achieved in the development of herbicides targeting the interruption of pigment biosynthesis, the discovery of efficient and selective herbicides bearing fundamentally new structures is still in high demand. Innovations and modifications of the carboxylic acid derivatives are some of the most effective and significant ways to search for novel structures as pigment inhibitory herbicides.…”