{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T13:25:31Z","timestamp":1788960331255,"version":"build-2803163510"},"reference-count":63,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2026,3,6]],"date-time":"2026-03-06T00:00:00Z","timestamp":1772755200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,3,6]],"date-time":"2026-03-06T00:00:00Z","timestamp":1772755200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["scijournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Pest Management Science"],"published-print":{"date-parts":[[2026,7]]},"abstract":"Abstract<\/jats:title>\n \n BACKGROUND<\/jats:title>\n \n Spodoptera frugiperda<\/jats:italic>\n (\n S. frugiperda<\/jats:italic>\n ) and\n Plutella xylostella<\/jats:italic>\n (\n P. xylostella<\/jats:italic>\n ) are major constraints to staple and cruciferous crops, respectively, and have evolved widespread resistance to anthranilic amide insecticides. Isoxazolines, acting as\n \u03b3<\/jats:italic>\n \u2010aminobutyric acid (GABA) receptor modulators, are promising alternatives for controlling resistant populations. However, many members of this class exhibit high toxicity toward ecologically important pollinators. Here, we report a series of new isoxazoline analogues featuring a 1,2,4\u2010oxadiazole motif designed by a ring\u2010closure strategy to the fluxametamide scaffold, and we systematically assess their insecticidal efficacy, honeybee toxicity, and interaction with receptors.\n <\/jats:p>\n <\/jats:sec>\n \n RESULTS<\/jats:title>\n \n Incorporation of a 1,2,4\u2010oxadiazole moiety enabled the design, synthesis, and bioevaluation of 34 novel derivatives. Compound\n L1<\/jats:bold>\n displayed potent activity against\n P<\/jats:italic>\n .\n xylostella<\/jats:italic>\n , with a median lethal concentration (LC\n 50<\/jats:sub>\n ) of 0.89\u2009mg\u2009L\n \u22121<\/jats:sup>\n . After chiral resolution,\n \n S<\/jats:italic>\n \u2010(+)\u2010L1\n <\/jats:bold>\n showed markedly enhanced potency (LC\n 50<\/jats:sub>\n \u2009=\u20090.69\u2009mg\u2009L\n \u22121<\/jats:sup>\n ), being 159.36\u2010fold more active than\n \n R<\/jats:italic>\n \u2010(\u2212)\u2010L1\n <\/jats:bold>\n (LC\n 50<\/jats:sub>\n \u2009=\u2009109.96\u2009mg\u2009L\n \u22121<\/jats:sup>\n ) and comparable to fluxametamide (LC\n 50<\/jats:sub>\n \u2009=\u20090.51\u2009mg\u2009L\n \u22121<\/jats:sup>\n ). Notably,\n \n S<\/jats:italic>\n \u2010(+)\u2010L1\n <\/jats:bold>\n exhibited substantially reduced acute contact toxicity to honeybees (LD\n 50<\/jats:sub>\n \u2009=\u20094.58\u2009\u03bcg a.i.\/bee) relative to fluxametamide (LD\n 50<\/jats:sub>\n \u2009=\u20090.25\u2009\u03bcg a.i.\/bee). Enzyme\u2010linked immunosorbent assay (ELISA)\u2010based assays and molecular docking suggested that\n \n S<\/jats:italic>\n \u2010(+)\u2010L1\n <\/jats:bold>\n binds more favorably to the pest GABA receptor than its enantiomer, while the 1,2,4\u2010oxadiazole unit specifically weakens hydrogen\u2010bond interactions with the bee GABA receptor, thereby mitigating toxicity.\n <\/jats:p>\n <\/jats:sec>\n \n CONCLUSION<\/jats:title>\n \n \n S<\/jats:italic>\n \u2010(+)\u2010L1\n <\/jats:bold>\n is identified as a selective lead combining high pesticidal potency with improved pollinator safety, suggesting ring\u2010closure\u2013enabled scaffold hopping as a viable strategy to retain on\u2010target engagement while enhancing non\u2010target compatibility. \u00a9 2026 Society of Chemical Industry.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1002\/ps.70708","type":"journal-article","created":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T16:36:59Z","timestamp":1772987819000},"page":"6272-6283","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Development of 1,2,4\u2010oxadiazole\u2010containing isoxazoline insecticides with improved honeybee compatibility"],"prefix":"10.1002","volume":"82","author":[{"given":"Qiu","family":"Liu","sequence":"first","affiliation":[{"name":"State Key Laboratory of Green Pesticide Center for R&D of Fine Chemicals of Guizhou University Guiyang P. 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