Discovery of Novel Isoxazoline Derivatives Containing Diaryl Ether against Fall Armyworms

With the continuous evolution of insect resistance, it
is a tremendous
challenge to control the fall armyworm (Spodoptera
frugiperda) with traditional insecticides. To solve
this pending issue, a series of novel isoxazoline derivatives containing
diaryl ether structures were designed and synthesized, and most of
the target compounds exhibited excellent insecticidal activity. Based
on the three-dimensional quantitative structure–activity relationship
(3D-QSAR) model analysis, we further optimized the molecular structure
with compound L35 obtained and tested for its activity.
Compound L35 (LC50 = 1.69 mg/L) exhibited
excellent insecticidal activity against S. frugiperda, which was better than those of commercial fipronil (LC50 = 70.78 mg/L) and indoxacarb (LC50 = 5.37 mg/L). The
enzyme-linked immunosorbent assay showed that L35 could
upregulate the levels of GABA in insects. In addition, molecular docking
and transcriptomic results also indicated that compound L35 may affect the nervous system of S. frugiperda by acting on GABA receptors. Notably, through high-performance liquid
chromatography (HPLC), we were able to obtain the two enantiomers
of compound L35, and the insecticidal activity test revealed
that S-(+)-L35 was 44 times more active
than R-(−)-L35 against S. frugiperda. This study established the chemistry
basis and mechanistic foundations for the future development of pesticide
candidates against fall armyworms.