A Versatile Natural Neolignan as a Potential Pesticide Resource: Synthesis and Insecticidal Evaluation of Honokiol Derivatives Featuring a Bis(benzoxazole) Scaffold

Inspired by the insecticidal scaffold honokiol, bis(benzoxazole)-fused analogs were designed and synthesized. Compounds 5h, 7d, 8f, 8m, and 9a exhibited potent oral toxicity (LC50 = 3.2–12.6 mg/L) and antifeedant activity (AFC50 = 1.0–3.3 mg/L) against Plutella xylostella, outperforming honokiol, toosendanin, and rotenone. In greenhouse trials, compound 8f (100 mg/L, 48 h) achieved 51.1% corrected mortality and 75.8% leaf protection. Against Mythimna separata, compounds 5f, 6f, 6n, 7a, and 8g showed pronounced growth inhibition (LC50 = 90–360 mg/L), exceeding honokiol and toosendanin. Acetylcholinesterase (AChE) was identified as a potential target in P. xylostella, and Chitinase inhibition disrupted M. separata development. Negligible cytotoxicity (IC50 > 100 μM) against the human keratinocyte cell line (HaCaT) suggests a favorable safety profile for mammalian exposure. The novel architectures, potent efficacy, and good safety profile highlight the potential of these honokiol-inspired compounds as promising insecticidal candidates.