{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T13:57:29Z","timestamp":1790776649136,"version":"4.1.0"},"reference-count":37,"publisher":"American Chemical Society (ACS)","issue":"38","license":[{"start":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T00:00:00Z","timestamp":1789603200000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T00:00:00Z","timestamp":1789603200000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T00:00:00Z","timestamp":1789603200000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-045"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32272590"],"award-info":[{"award-number":["32272590"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/na","name":"Central Government Guides Local Science and Technology Development Fund Projects","doi-asserted-by":"publisher","award":["2024007"],"award-info":[{"award-number":["2024007"]}],"id":[{"id":"10.13039\/na","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,9,30]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Spodoptera frugiperda is a highly destructive pest with widespread resistance to conventional insecticides. Mesoionic chemicals are promising for insecticide discovery, yet lepidopteran-active examples remain limited and many raise pollinator-safety concerns. Here, we report a series of pyrazole-decorated mesoionic pyrido[1,2-a]pyrimidine derivatives and identify Q4 as a lepidopteran-active insecticide candidate with potent activity against S. frugiperda, although its potency is slightly lower than that of the commercial standard dicloromezotiaz. Q4 exhibits relatively lower acute contact toxicity toward honeybees, with an acute contact LD50 of 9.83 \u03bcg a.i.\/bee compared with 0.747 \u03bcg a.i.\/bee for dicloromezotiaz. ELISA, enzyme activity assays, and electrophysiological recordings reveal that Q4 disrupts neuronal homeostasis and inhibits nAChR-mediated currents. RT-qPCR and RNA interference assays implicate \u03b11- and \u03b22-containing nAChR subunits as key determinants of activity. This work identifies Q4 as a lepidopteran-active, comparatively honeybee-safer mesoionic lead and provides a basis for sustainable pest management.<\/jats:p>","DOI":"10.1021\/acs.jafc.6c01122","type":"journal-article","created":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T15:02:18Z","timestamp":1789657338000},"page":"29857-29868","source":"Crossref","is-referenced-by-count":0,"title":["A Honeybee-Safer\nPyrazolyl Pyrido[1,2-\n                    <i>a<\/i>\n                    ]pyrimidine Mesoionic\nTargeting Fall Armyworm nAChR \u03b11\/\u03b22\nSubunits"],"prefix":"10.1021","volume":"74","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-9968-6500","authenticated-orcid":true,"given":"Ruilan","family":"Wang","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\/0009-0000-2768-8464","authenticated-orcid":true,"given":"Huan","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\/0000-0003-0456-4076","authenticated-orcid":true,"given":"Qingqing","family":"Ma","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\/0000-0002-4237-6167","authenticated-orcid":true,"given":"Baoan","family":"Song","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\/0000-0003-2502-778X","authenticated-orcid":true,"given":"Runjiang","family":"Song","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"}]}],"member":"316","published-online":{"date-parts":[[2026,9,17]]},"reference":[{"key":"2026093009071373600_cit1","doi-asserted-by":"publisher","first-page":"646","DOI":"10.1016\/S2095-3119(20)63367-6","article-title":"Biology, invasion\nand management of the agricultural invader: Fall armyworm, Spodoptera frugiperda (Lepidoptera: Noctuidae)","volume":"20","author":"Wan","year":"2021","journal-title":"J. Integr. Agric."},{"key":"2026093009071373600_cit2","doi-asserted-by":"publisher","DOI":"10.1016\/j.agee.2019.106804","article-title":"Spread and impact of fall armyworm\n(Spodoptera frugiperda J.E. Smith)\nin maize production areas of Kenya","volume":"292","author":"De Groote","year":"2020","journal-title":"Agric. Ecosyst.\nEnviron."},{"key":"2026093009071373600_cit3","doi-asserted-by":"publisher","DOI":"10.3389\/fagro.2025.1538198","article-title":"Fall armyworm\n(Spodoptera frugiperda) in Africa:\nInsights into biology, ecology and impact on staple crops, food systems\nand management approaches","volume":"7","author":"Togola","year":"2025","journal-title":"Front. Agron."},{"key":"2026093009071373600_cit4","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-25505-7","article-title":"Climate warming promotes pesticide\nresistance through\nexpanding overwintering range of a global pest","volume":"12","author":"Ma","year":"2021","journal-title":"Nat. Commun."},{"key":"2026093009071373600_cit5","doi-asserted-by":"publisher","first-page":"666","DOI":"10.1016\/j.oneear.2021.04.015","article-title":"Unwelcome\nexchange: International trade as a direct and indirect driver of biological\ninvasions worldwide","volume":"4","author":"Hulme","year":"2021","journal-title":"One Earth."},{"key":"2026093009071373600_cit6","doi-asserted-by":"publisher","first-page":"2609","DOI":"10.1002\/ps.6254","article-title":"Insecticide\nresistance management and industry: The origins and evolution of the\nInsecticide Resistance Action Committee (IRAC) and the mode of action\nclassification scheme","volume":"77","author":"Sparks","year":"2021","journal-title":"Pest Manage. Sci."},{"key":"2026093009071373600_cit7","doi-asserted-by":"publisher","DOI":"10.34133\/research.0637","article-title":"Carbene-catalyzed\nphthalide ether functionalization for discovering chiral phytovirucide\nthat specifically targets viral Nia protein to inhibit proliferation","volume":"8","author":"Wang","year":"2025","journal-title":"Research"},{"key":"2026093009071373600_cit8","unstructured":"Michigan State University.\n          . Arthropod Pesticide Resistance Database\n(APRD). https:\/\/www.pesticideresistance.org\/. (accessed January 2,\n2026)."},{"key":"2026093009071373600_cit9","doi-asserted-by":"publisher","first-page":"4677","DOI":"10.1002\/ps.8827","article-title":"Characterization\nof cyantraniliprole resistance in Spodoptera frugiperda: Selection, inheritance pattern, and cross-resistance to other diamide\ninsecticides","volume":"81","author":"Thiesen","year":"2025","journal-title":"Pest Manag. Sci."},{"key":"2026093009071373600_cit10","doi-asserted-by":"publisher","first-page":"911","DOI":"10.1016\/j.bmcl.2017.01.002","article-title":"Mesoionic\npyrido[1,2-a]pyrimidinones: Discovery of dicloromezotiaz\nas a lepidoptera insecticide\nacting on nicotinic acetylcholine receptors","volume":"27","author":"Zhang","year":"2017","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"2026093009071373600_cit11","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1016\/j.bmcl.2016.11.042","article-title":"Mesoionic\npyrido[1,2-a]pyrimidinones: Discovery of triflumezopyrim\nas a potent\nhopper insecticide","volume":"27","author":"Zhang","year":"2017","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"2026093009071373600_cit12","doi-asserted-by":"publisher","first-page":"2381","DOI":"10.1021\/acs.accounts.7b00311","article-title":"Mesoionic\npyrido[1,2-a]pyrimidinone insecticides: From discovery\nto triflumezopyrim and dicloromezotiaz","volume":"50","author":"Zhang","year":"2017","journal-title":"Acc.\nChem. Res."},{"key":"2026093009071373600_cit13","doi-asserted-by":"publisher","first-page":"11039","DOI":"10.1021\/acs.jafc.0c02376","article-title":"Recent research progress in and perspectives\nof mesoionic insecticides: Nicotinic acetylcholine receptor inhibitors","volume":"68","author":"Liu","year":"2020","journal-title":"J. Agric. Food Chem."},{"key":"2026093009071373600_cit14","doi-asserted-by":"publisher","first-page":"312","DOI":"10.1016\/j.eng.2025.11.028","article-title":"The tiny but marvelous methyl group in insecticide\ndiscovery: A perspective","volume":"59","author":"Liu","year":"2025","journal-title":"Engineering"},{"key":"2026093009071373600_cit15","doi-asserted-by":"publisher","first-page":"32","DOI":"10.1016\/j.ibmb.2016.04.008","article-title":"Mode of action of triflumezopyrim: A novel mesoionic\ninsecticide which inhibits the nicotinic acetylcholine receptor","volume":"74","author":"Cordova","year":"2016","journal-title":"Insect Biochem. Mol. Biol."},{"key":"2026093009071373600_cit16","unstructured":"Guideline for laboratory bioassay of pesticides Part 10:\nDiet incorporation\nmethod (NY\/T 1154.10-2008), Ministry of Agriculture\nof the People\u2019s Republic of Chinahttps:\/\/std.samr.gov.cn\/hb. 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(accessed January 1, 2026)."},{"key":"2026093009071373600_cit20","unstructured":"Office of Pesticide\nPrograms. Guidance for Assessing Pesticide Risks\nto Bees, U.S. Environmental Protection Agency(EPA)https:\/\/www.epa.gov\/sites\/default\/files\/2014-06\/documents\/pollinator_risk_assessment_guidance_06_19_14.pdf (accessed 14 October 2025)."},{"key":"2026093009071373600_cit21","doi-asserted-by":"publisher","first-page":"535","DOI":"10.1242\/jeb.144.1.535","article-title":"Ionic species involved in the electrical\nactivity of single aminergic neurones isolated from the sixth abdominal\nganglion of the cockroach Periplaneta americana","volume":"144","author":"Lapied","year":"1989","journal-title":"J. Exp. Biol."},{"key":"2026093009071373600_cit22","first-page":"1098","article-title":"Cloning of nicotinic\nacetylcholine receptor \u03b16 and \u03b17 subunit genes in Spodoptera frugiperda ( Lepidoptera: Noctuidae) and their response to spinetoram stress","volume":"65","author":"Gao","year":"2022","journal-title":"Acta Entomol. Sin."},{"key":"2026093009071373600_cit23","doi-asserted-by":"publisher","first-page":"6889","DOI":"10.1021\/acs.jafc.3c06531","article-title":"miR-317-3p and miR-283-5p\nplay a crucial role in regulating the resistance to indoxacarb in Spodoptera frugiperda by targeting GSTs4","volume":"72","author":"Wu","year":"2024","journal-title":"J. Agric. Food Chem."},{"key":"2026093009071373600_cit24","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1007\/978-1-0716-3441-7_6","article-title":"Protein-Ligand blind docking\nusing CB-Dock2","volume-title":"Computational Drug Discovery\nand Design","author":"Liu","year":"2024"},{"key":"2026093009071373600_cit25","doi-asserted-by":"publisher","DOI":"10.1016\/j.compbiolchem.2025.108358","article-title":"In silico\nanalysis of novel Triacontafluoropentadec-1-ene as a sustainable replacement\nfor dodecane in fisheries microplastics: Molecular docking, dynamics\nsimulation and pharmacophore studies of acetylcholinesterase activity","volume":"115","author":"Thakur","year":"2025","journal-title":"Comput. Biol. Chem."},{"key":"2026093009071373600_cit26","unstructured":"Zhang, W. M.; Holyoke, C. W., Jr.; Hughes, K. A.; Lahm, G. P.; Pahutski, T. F., Jr.; Tong, M.-H. T.; Xu, M.\n          Mesoionic pesticides. WO Patent WO2011\/017342A2, 2011."},{"key":"2026093009071373600_cit27","doi-asserted-by":"publisher","DOI":"10.1016\/j.pestbp.2024.106269","article-title":"Influence of triflumezopyrim\nand triadimefon co-exposure on enzymatic activity and gene expression\nchanges in honey bees (Apis melliferaL.)","volume":"208","author":"Liu","year":"2025","journal-title":"Pestic. Biochem. Physiol."},{"key":"2026093009071373600_cit28","doi-asserted-by":"publisher","first-page":"7793","DOI":"10.1002\/ps.70094","article-title":"Innovative\npyrido[1,2-a]pyrimidine-based cinnamic acid derivatives\nagainst Sogatella furcifera with better\nbiosafety to pollinators","volume":"81","author":"Wang","year":"2025","journal-title":"Pest Manag. Sci."},{"key":"2026093009071373600_cit29","doi-asserted-by":"publisher","first-page":"17432","DOI":"10.1021\/acs.jafc.5c01089","article-title":"Isoxazole-based\noptimization of pyrido[1,2-a]pyrimidine mesoionic\ncompounds for discovering aphicidal molecules tolerated by honeybees","volume":"73","author":"Yang","year":"2025","journal-title":"J. Agric. Food Chem."},{"key":"2026093009071373600_cit30","doi-asserted-by":"publisher","first-page":"914","DOI":"10.1002\/ps.349","article-title":"Structure and diversity of insect\nnicotinic acetylcholine\nreceptors","volume":"57","author":"Tomizawa","year":"2001","journal-title":"Pest Manage. Sci."},{"key":"2026093009071373600_cit31","doi-asserted-by":"publisher","DOI":"10.1016\/j.pestbp.2025.106532","article-title":"The mode\nof action of neonicotinoids and related compounds on insect neuronal\nnicotinic acetylcholine receptors highlights complex intracellular\ncalcium mechanisms","volume":"213","author":"Thany","year":"2025","journal-title":"Pestic. Biochem. Physiol."},{"key":"2026093009071373600_cit32","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1010522","article-title":"Functional\nimpact of subunit composition\nand compensation on Drosophila melanogaster nicotinic receptors-targets of neonicotinoids","volume":"19","author":"Komori","year":"2023","journal-title":"PLoS Genet."},{"key":"2026093009071373600_cit33","doi-asserted-by":"publisher","first-page":"239","DOI":"10.1016\/j.neuro.2017.08.001","article-title":"Subchronic exposure to sublethal\ndose of imidacloprid\nchanges electrophysiological properties and expression pattern of\nnicotinic acetylcholine receptor subtypes in insect neurosecretory\ncells","volume":"62","author":"Benzidane","year":"2017","journal-title":"Neurotoxicology"},{"key":"2026093009071373600_cit34","doi-asserted-by":"publisher","first-page":"102","DOI":"10.1093\/jisesa\/iev080","article-title":"Transcriptional\nchanges in nAChRs, interactive proteins and P450s in Locusta migratoria manilensis (Orthoptera: Acrididae) CNS in response\nto high and low oral doses of imidacloprid","volume":"15","author":"Wang","year":"2015","journal-title":"J. Insect Sci."},{"key":"2026093009071373600_cit35","doi-asserted-by":"publisher","DOI":"10.1016\/j.pestbp.2022.105191","article-title":"CRISPR-mediated\nknockout of nicotinic acetylcholine receptor (nAChR) \u03b16 subunit confers high levels of resistance to spinosyns in Spodoptera frugiperda","volume":"187","author":"Shi","year":"2022","journal-title":"Pestic.\nBiochem. Physiol."},{"key":"2026093009071373600_cit36","doi-asserted-by":"publisher","first-page":"12176","DOI":"10.1021\/acs.jafc.5c01017","article-title":"Multiple mutations in the \u03b21\nsubunit of the nicotinic\nacetylcholine receptor confer resistance to neonicotinoids","volume":"73","author":"Cheng","year":"2025","journal-title":"J. Agric. Food Chem."},{"key":"2026093009071373600_cit37","unstructured":"Boitreaud, J.; Dent, J.; McPartlon, M.; Meier, J.; Reis, V.; Rogozhonikov, A.; Wu, K.; Chai Discovery team.. Chai-1: Decoding\nthe molecular interactions of lifebioRxiv202410.1101\/2024.10.10.615955."}],"container-title":["Journal of Agricultural\nand Food Chemistry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/acs.jafc.6c01122","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/jafcau\/article-pdf\/74\/38\/29857\/68545301\/acs.jafc.6c01122.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/jafcau\/article-pdf\/74\/38\/29857\/68545301\/acs.jafc.6c01122.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T13:11:58Z","timestamp":1790773918000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/jafcau\/article\/74\/38\/29857\/5432079\/A-Honeybee-Safer-Pyrazolyl-Pyrido-1-2-a-pyrimidine"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,17]]},"references-count":37,"journal-issue":{"issue":"38","published-online":{"date-parts":[[2026,9,17]]},"published-print":{"date-parts":[[2026,9,30]]}},"URL":"https:\/\/doi.org\/10.1021\/acs.jafc.6c01122","relation":{},"ISSN":["0021-8561","1520-5118"],"issn-type":[{"value":"0021-8561","type":"print"},{"value":"1520-5118","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,17]]}}}