Rational Design, Structural Optimization, Synthesis, Biological Assessment, and Theoretical Validation of Novel...

Area of Science:

• Agricultural Science
• Medicinal Chemistry
• Biochemistry

Background:

• 4-Hydroxyphenylpyruvate dioxygenase (HPPD) is a key enzyme targeted in herbicide development.
• Existing herbicides face challenges with resistance and environmental impact, necessitating novel inhibitor discovery.

Purpose of the Study:

• To design and synthesize novel 3-aroylpyridine-2,4(1H,3H)-diones as potential HPPD inhibitors.
• To evaluate the herbicidal activity and crop safety of the synthesized compounds.
• To elucidate the binding mechanism and structure-activity relationships of potent inhibitors.

Main Methods:

• Synthesis of 48 triketone derivatives (III-1-III-48) via a one-pot procedure.
• In vitro inhibition assays against Arabidopsis thaliana HPPD (AtHPPD).
• Molecular docking, molecular dynamics simulations, and Density Functional Theory (DFT) calculations.

Main Results:

• Compound III-22 demonstrated potent AtHPPD inhibition (IC50 = 0.210 μM), surpassing the reference mesotrione.
• Herbicidal activity >90% against tested weeds at 200 g a.i./ha with no significant phytotoxicity in major crops at 300 g a.i./ha.
• Molecular modeling confirmed stable binding of III-22 to AtHPPD through chelation and π-π stacking interactions.

Conclusions:

• Aroyl-substituted pyridinones are effective HPPD inhibitors and promising herbicide candidates.
• Compound III-22 exhibits high efficacy and crop safety, suitable for sustainable weed management.
• Structure-activity relationship analysis provides insights for future herbicide design.