Discovery of Novel Pyrazole-Benzothiazine Hybrids as Potential HPPD Inhibitors

Area of Science:

• Agricultural Chemistry
• Medicinal Chemistry
• Biochemistry

Background:

• 4-Hydroxyphenylpyruvate dioxygenase (HPPD) is a crucial target for developing new herbicides.
• Existing herbicides like topramezone and mesotrione target HPPD.
• There is a need for novel HPPD inhibitors with improved efficacy and selectivity.

Purpose of the Study:

• To design and synthesize novel pyrazole-benzothiazine hybrids as potential HPPD inhibitors.
• To evaluate the herbicidal activity and crop safety of the synthesized compounds.
• To investigate the binding mechanism of the most potent inhibitors with HPPD.

Main Methods:

• Chemical synthesis of pyrazole-benzothiazine hybrids using combination and enol tautomerism strategies.
• In vitro bioassays to determine inhibition of Arabidopsis thaliana HPPD (AtHPPD) and herbicidal activity against weeds.
• Molecular docking simulations to predict binding modes.
• Microscale thermophoresis (MST) and fluorescence titration (FT) to confirm binding affinity.

Main Results:

• Compound A3 exhibited strong inhibition of AtHPPD (IC50 = 0.06 μM), significantly outperforming topramezone and mesotrione.
• Compound B10 demonstrated over 80% herbicidal activity at 150 g a.i./ha with low injury to maize, peanut, and cotton.
• Molecular docking and biophysical methods confirmed strong binding affinity of A3 and B10 to AtHPPD, involving chelation, π-π interactions, and hydrogen bonds with Asn282.

Conclusions:

• Pyrazole-benzothiazine hybrids represent a promising scaffold for the development of novel HPPD inhibitors.
• The synthesized compounds show potential for effective weed control with good crop selectivity.
• Further research into this chemical class could lead to next-generation herbicides.