Pests
represent an important impediment to efficient agricultural
production and pose a threat to global food security. On the basis
of our prior research focused on identifying insecticidal leads targeting
insect ryanodine receptors (RyRs), we aimed to identify evodiamine
scaffold-based novel insecticides. Thus, a variety of evodiamine-based
derivatives were designed, synthesized, and assessed for their insecticidal
activity against the larvae of Mythimna separata (M. separata) and Plutella xylostella (P. xylostella). The preliminary bioassay results revealed that more than half
of the target compounds exhibited superior activity compared to evodiamine,
matrine, and rotenone against M. separata. Among these, compound 21m displayed the most potent
larvicidal efficiency, with a remarkable mortality rate of 93.3% at
2.5 mg/L, a substantial improvement over evodiamine (10.0% at 10 mg/L),
matrine (10.0% at 200 mg/L), and rotenone (30.0% at 200 mg/L). In
the case of P. xylostella, compounds 21m and 21o displayed heightened larvicidal activity,
boasting LC50 values of 9.37 × 10–2 and 0.13 mg/L, respectively, surpassing that of evodiamine (13.41
mg/L), matrine (291.78 mg/L), and rotenone (18.39 mg/L). A structure–activity
relationship analysis unveiled that evodiamine-based derivatives featuring
a cyclopropyl sulfonyl group at the nitrogen atom of the B ring and
a fluorine atom in the E ring exhibited more potent larvicidal effects.
This finding was substantiated by calcium imaging experiments and
molecular docking, which suggested that 21m could target
insect RyRs, including resistant mutant RyRs of P.
xylostella (G4946E and I4790M), with higher affinity
than chlorantraniliprole (CHL). Additionally, cytotoxicity assays
highlighted that the potent compounds 21i, 21m, and 21o displayed favorable selectivity and low toxicity
toward nontarget organisms. Consequently, compound 21m emerges as a promising candidate for further development as an insecticide
targeting insect RyRs.