Natural Biphenyl-Type Neolignans as Resources of Pesticide Candidates: Assembly, Insecticidal Potency, and Cytotoxicity of Honokiol/Magnolol Analogues of Isoxazoline Hybridization via [3 + 2] Dipolar Cycloaddition

Currently, the development of novel pesticides remains a crucial initiative to address the challenges of agricultural pest management. In pursuit of agrochemical candidates derived from plant natural products (NPs), 76 novel isoxazoline-hybridized honokiol/magnolol analogues were assembled via a [3 + 2] dipolar cycloaddition reaction, and their pesticidal potency and cytotoxicity were evaluated. Bioassays revealed that 13 compounds (<b>5d</b>, <b>6k</b>, <b>7b</b>-<b>d</b>, <b>7f</b>, <b>7g</b>, <b>8d</b>-<b>f</b>, <b>13f</b>, <b>15d</b>, and <b>16h</b>) exhibited superior larvicidal activity against <i>Plutella xylostella</i> Linnaeus with LC₅₀ values in the range of 1.75-5.87 μg/mL, outperforming the botanical insecticide rotenone (LC₅₀ = 26.7 μg/mL). Particularly, compounds <b>7c</b>, <b>8d</b>, and <b>15d</b> showed over 11-fold higher larvicidal activity against <i>P. xylostella</i> than against rotenone. Meanwhile, compounds <b>5i</b>, <b>6g</b>, <b>7a</b>, and <b>8a</b> displayed better growth inhibitory effects on <i>Mythimna separata</i> Walker (LC₅₀ = 0.13, 0.25, 0.34, and 0.35 mg/mL, respectively) compared to rotenone (LC₅₀ = 0.53 mg/mL). Further greenhouse potted-plant assays revealed that compounds <b>8d</b> and <b>15d</b> showed superior <i>in vivo</i> control efficacy against <i>P. xylostella</i> compared to rotenone and comparable to tolfenpyrad and also demonstrated good protective effects on plants. Toxicity tests disclosed that these potent compounds exhibited moderate cytotoxicity to the human keratinocyte cell line (HaCaT), indicating a considerably favorable safety profile for skin exposure. Structure-activity relationship (SAR) analysis illustrated the importance of the exposed hydroxyls and newly introduced isoxazoline scaffolds in enhancing the insecticidal activity of these compounds. The novel scaffold, excellent insecticidal potency, and good safety profile position these compounds reported herein as promising leads for further pesticide candidates development. Furthermore, the present work offers valuable insights for advancing the NP-inspired agrochemical innovation.