Herbicide safeners enhance herbicide detoxification in crops without
reducing their herbicidal efficacy against target weeds. To alleviate
maize injury caused by the sulfonylurea herbicide nicosulfuron, a
series of 1,3-disubstituted imidazolidine or hexahydropyrimidine derivatives
were rationally designed via bioisosterism and active subunit combinations.
Thirty novel compounds were synthesized using an efficient one-pot
method and low-cost raw materials and characterized by IR, 1H NMR, 13C NMR, and high-resolution mass spectrometer
(HRMS). Bioactivity and structure–activity relationship (SAR)
were evaluated for herbicide safeners tested against nicosulfuron
injury. Most of the compounds effectively protected sensitive maize
against nicosulfuron damage. The parent skeletons and substituents
of the target compounds both substantially influenced their safener
activity. Compound I-3 exhibited superior bioactivity
compared to the safener isoxadifen-ethyl. Molecular docking simulations
disclosed that compound I-3 competed with nicosulfuron
for the acetolactate synthase active site and demonstrated that this
is the protective mechanism of safeners. The target compound I-3 presented with strong herbicide safener activity in maize
and is, therefore, a potential candidate for the development of a
novel herbicide safener.
Nicosulfuron is the leading herbicide in the global sulfonylurea
(SU) herbicide market; it was jointly developed by DuPont and Ishihara.
Recently, the widespread use of nicosulfuron has led to increasingly
prominent agricultural production hazards, such as environmental harm
and influence on subsequent crops. The use of herbicide safeners can
significantly alleviate herbicide injury to protect crop plants and
expand the application scope of existing herbicides. A series of novel
aryl-substituted formyl oxazolidine derivatives were designed using
the active group combination method. Title compounds were synthesized
using an efficient one-pot method and characterized by infrared (IR)
spectrometry, 1H and 13C nuclear magnetic resonance
(NMR), and high-resolution mass spectrometry (HRMS). The chemical
structure of compound V-25 was further identified by
X-ray single crystallography. The bioactivity assay and structure–activity
relationship proved that nicosulfuron phytotoxicity to maize could
be reduced by most title compounds. The glutathione S-transferase (GST) activity and acetolactate synthase (ALS) in vivo were determined, and compound V-12 showed
inspiring activity comparable to that of the commercial safener isoxadifen-ethyl.
The molecular docking model indicated that compound V-12 competed with nicosulfuron for the acetolactate synthase active
site and that this is the protective mechanism of safeners. Absorption,
distribution, metabolism, excretion, and toxicity (ADMET) predictions
demonstrated that compound V-12 exhibited superior pharmacokinetic
properties to the commercialized safener isoxadifen-ethyl. The target
compound V-12 shows strong herbicide safener activity
in maize; thus, it may be a potential candidate compound that can
help further protect maize from herbicide damage.
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