Rational Design of β-Ketonitrile Acaricides through Binding-Mode-Guided Isosteric Ring Replacement

Area of Science:

• Agricultural Chemistry
• Entomology
• Toxicology

Background:

• β-Ketonitrile acaricides are crucial for controlling phytophagous mites by targeting succinate dehydrogenase (SDH).
• Developing novel derivatives is essential for effective mite management and overcoming resistance.
• SDH inhibitors (SDHIs) are a significant class of agrochemicals with broad applications.

Purpose of the Study:

• To rationally design novel β-ketonitrile acaricides using a binding mode similarity-based isosteric ring replacement strategy.
• To identify potent acaricidal compounds with an improved safety profile.
• To investigate the mechanism of action of the designed compounds.

Main Methods:

• Applied a structure-based drug design approach incorporating isosteric ring replacement.
• Synthesized arylcarbonitrile and arylacrylonitrile derivatives containing SDHI fungicidal moieties.
• Evaluated acaricidal activity against various developmental stages of *Tetranychus cinnabarinus* and assessed acute fish toxicity.

Main Results:

• The optimal compound, A23 (3-trifluoromethyl-1*H*-methylpyrazole moiety), demonstrated high efficacy against adult, nymph, and egg stages of *Tetranychus cinnabarinus*.
• Compound A23 exhibited significantly lower acute fish toxicity (3.2-fold decrease) compared to cyenopyrafen.
• Mechanism studies confirmed SDH inhibition via conserved cation-π interactions and H-bonds.

Conclusions:

• The designed β-ketonitrile acaricides, particularly A23, show excellent acaricidal activity and a favorable ecological safety profile.
• These findings provide a potential candidate for developing new acaricides and offer insights for designing other SDHI agrochemicals.
• The study highlights the success of a rational design strategy for novel pesticide development.