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We herein describe a set of new pyrido[1,2-a]pyrimidinone derivatives bearing a carbamate moiety attached via a methylene spacer at the 2-position. Insecticidal bioassays identified H3 as the most potent analogue against M. crassicauda, comparable to the commercial standard TFM. Encouragingly, H3 exhibited remarkably low toxicity to honeybees, with acute oral and contact LD50 values of 24.0 and 35.1 \u03bcg a.i.\/bee, respectively, which were markedly higher than those of TFM. Mechanistic studies combining proteomics, enzymatic assays, and molecular docking consistently suggested that H3 disrupts neuronal homeostasis via interfering with nAChR and AChE activity, leading to insect mortality. This work provides a promising and bee-safe lead for sustainable pest management, offering a new molecular template for the development of highly selective insecticides.<\/jats:p>","DOI":"10.1021\/acs.jafc.5c18072","type":"journal-article","created":{"date-parts":[[2026,8,22]],"date-time":"2026-08-22T10:00:00Z","timestamp":1787392800000},"page":"26956-26968","source":"Crossref","is-referenced-by-count":0,"title":["Carbamate-Modified\nPyrido[1,2-\n                    <i>a<\/i>\n                    ]pyrimidinones: Design and Synthesis\nof Insecticides with High Efficacy\nand Low Bee Toxicity"],"prefix":"10.1021","volume":"74","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0456-4076","authenticated-orcid":true,"given":"Qingqing","family":"Ma","sequence":"first","affiliation":[{"name":"Center for R&D of Fine Chemicals of Guizhou University , , ,","place":["Guiyang, P. R. China, 550025"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2220-7518","authenticated-orcid":true,"given":"Shang","family":"Wu","sequence":"additional","affiliation":[{"name":"Center for R&D of Fine Chemicals of Guizhou University , , ,","place":["Guiyang, P. R. China, 550025"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0808-5320","authenticated-orcid":true,"given":"Luoman","family":"Zhang","sequence":"additional","affiliation":[{"name":"Center for R&D of Fine Chemicals of Guizhou University , , ,","place":["Guiyang, P. R. China, 550025"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-9968-6500","authenticated-orcid":true,"given":"Ruilan","family":"Wang","sequence":"additional","affiliation":[{"name":"Center for R&D of Fine Chemicals of Guizhou University , , ,","place":["Guiyang, P. R. 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Mater."},{"key":"2026090311501323400_cit49","doi-asserted-by":"publisher","first-page":"2297","DOI":"10.1021\/acs.jmedchem.1c01767","article-title":"Structural\nBiology-Guided Design, Synthesis, and Biological Evaluation of Novel\nInsect Nicotinic Acetylcholine Receptor Orthosteric Modulators","volume":"65","author":"Montgomery","year":"2022","journal-title":"J. Med. Chem."},{"issue":"5","key":"2026090311501323400_cit50","doi-asserted-by":"publisher","first-page":"2269","DOI":"10.1016\/j.apsb.2023.02.018","article-title":"Nimbolide targeting SIRT1 mitigates\nintervertebral disc degeneration by reprogramming cholesterol metabolism\nand inhibiting inflammatory signaling","volume":"13","author":"Teng","year":"2023","journal-title":"Acta\nPharm. Sin. 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