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However, few TPP inhibitors have been reported, and broad-spectrum agents targeting both insects and fungi remain scarce. In this study, 2-cinnamoylbenzimidazole was identified as a dual-targeting inhibitor scaffold against insect and fungal TPPs. Structure-guided optimization by pocket size yielded 5\u20131 (Ki = 1.3 \u03bcM) for insect TPP and 5\u20133 (Ki = 17.3 \u03bcM) for fungal TPP. Molecular docking revealed that 2-cinnamoylbenzimidazole forms hydrogen bonds with conserved active-site residues, while its aryl ring occupies a hydrophobic subsite. Biological assays demonstrated that ingestion of 1 mM 5\u20131 caused 100% mortality in Plutella xylostella larvae and reduced locomotion in Locusta migratoria, concomitant with marked reductions in hemolymph trehalose and glucose. This work provides a novel TPP inhibitor scaffold, demonstrates a structure-guided optimization strategy, and establishes a foundation for developing multifunctional pesticides.<\/jats:p>","DOI":"10.1021\/acs.jafc.6c00444","type":"journal-article","created":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T19:02:19Z","timestamp":1786474939000},"page":"26787-26795","source":"Crossref","is-referenced-by-count":0,"title":["Discovery of 2-Cinnamoylbenzimidazoles\nas Novel\nInsect and Fungal Trehalose-6-Phosphate Phosphatase Inhibitors"],"prefix":"10.1021","volume":"74","author":[{"given":"Xi","family":"Jiang","sequence":"first","affiliation":[{"name":"Dalian University of Technology , , 2 Linggong Road , ,","place":["Dalian, China, 116024"]},{"name":"Dalian University , , 10 Xuefu Road , ,","place":["Dalian, China, 116622"]},{"name":"Institute of Plant Protection, Chinese Academy of Agricultural Sciences , , 2 West Yuanmingyuan Road , ,","place":["Beijing, China, 100193"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingjia","family":"Gao","sequence":"additional","affiliation":[{"name":"Dalian University of Technology , , 2 Linggong Road , ,","place":["Dalian, China, 116024"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3055-3426","authenticated-orcid":true,"given":"Zhijun","family":"Zhang","sequence":"additional","affiliation":[{"name":"Lanzhou University , , 222 South Tianshui Road , ,","place":["Lanzhou, China, 730000"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huitang","family":"Qi","sequence":"additional","affiliation":[{"name":"Dalian University of Technology , , 2 Linggong Road , ,","place":["Dalian, China, 116024"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Baoqi","family":"Zhang","sequence":"additional","affiliation":[{"name":"Lanzhou University , , 222 South Tianshui Road , ,","place":["Lanzhou, China, 730000"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7574-3990","authenticated-orcid":true,"given":"Dongli","family":"Wang","sequence":"additional","affiliation":[{"name":"China Agricultural University , , ,","place":["Beijing, China, 100193"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6319-1092","authenticated-orcid":true,"given":"Li","family":"Zhang","sequence":"additional","affiliation":[{"name":"China Agricultural University , , ,","place":["Beijing, China, 100193"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5825-5397","authenticated-orcid":true,"given":"Junfeng","family":"Liu","sequence":"additional","affiliation":[{"name":"China Agricultural University , , ,","place":["Beijing, China, 100193"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5600-0913","authenticated-orcid":true,"given":"Yingqian","family":"Liu","sequence":"additional","affiliation":[{"name":"Lanzhou University , , 222 South Tianshui Road , ,","place":["Lanzhou, China, 730000"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9768-5496","authenticated-orcid":true,"given":"Tian","family":"Liu","sequence":"additional","affiliation":[{"name":"Dalian University of Technology , , 2 Linggong Road , ,","place":["Dalian, China, 116024"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,8,11]]},"reference":[{"issue":"4","key":"2026090104471814300_cit1","doi-asserted-by":"publisher","first-page":"17R","DOI":"10.1093\/glycob\/cwg047","article-title":"New insights on trehalose:\na multifunctional molecule","volume":"13","author":"Elbein","year":"2003","journal-title":"Glycobiology"},{"key":"2026090104471814300_cit2","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1016\/j.ijbiomac.2021.07.096","article-title":"Characterization\nand expression pattern of the trehalose-6-phosphate\nsynthase and trehalose-6-phosphate phosphatase gene families in Populus","volume":"187","author":"Gao","year":"2021","journal-title":"Int. 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Insect Physiol."},{"issue":"4","key":"2026090104471814300_cit4","doi-asserted-by":"publisher","first-page":"262","DOI":"10.1093\/glycob\/cwad011","article-title":"Regulation of trehalose metabolism\nin insects: from genes to the metabolite window","volume":"33","author":"Tellis","year":"2023","journal-title":"Glycobiology"},{"key":"2026090104471814300_cit5","doi-asserted-by":"publisher","DOI":"10.1111\/1744-7917.70121","article-title":"Metabolic\nbenefits conferred by duplication of the facilitated trehalose transporter\nin Lepidoptera","author":"Zhong","year":"2025","journal-title":"Insect Sci."},{"issue":"3","key":"2026090104471814300_cit6","doi-asserted-by":"publisher","first-page":"718","DOI":"10.1111\/1744-7917.12819","article-title":"Inhibition\nof trehalase affects the trehalose and chitin metabolism pathways\nin Diaphorina citri (Hemiptera: Psyllidae)","volume":"28","author":"Yu","year":"2021","journal-title":"Insect Sci."},{"issue":"2","key":"2026090104471814300_cit7","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1128\/MMBR.00053-16","article-title":"Central\nrole of the trehalose biosynthesis pathway in the pathogenesis of\nhuman fungal infections: Opportunities and challenges for therapeutic\ndevelopment","volume":"81","author":"Thammahong","year":"2017","journal-title":"Microbiol. 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