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In vitro bioassay results indicated that some target compounds exhibited certain antifungal activity against the tested fungi at a concentration of 50 \u03bcg\/mL. Especially, compounds I-1, I-5, I-7, and I-12 demonstrated promising antifungal activity against C. arachidicola, R. solani, and S. sclerotiorum, with EC50 values ranging from 4.61 to 6.66 \u03bcg\/mL. Additionally, transcriptome analysis revealed that the molecular mode of action of compound I-12 involves the inhibition of nitrogen metabolism and the proteasome pathway. The present work demonstrates that 4,5,6,7-tetrahydrothieno [3,2-b] pyridine represents a promising lead scaffold and provides important theoretical foundations and innovative perspectives for the development of novel and highly efficient fungicides.<\/jats:p>","DOI":"10.3390\/microorganisms13071588","type":"journal-article","created":{"date-parts":[[2025,7,7]],"date-time":"2025-07-07T02:53:07Z","timestamp":1751856787000},"page":"1588","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Discovery of 4,5,6,7-Tetrahydrothieno [3,2-b] Pyridine as Novel Fungicide Lead Scaffold"],"prefix":"10.3390","volume":"13","author":[{"given":"Ke","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Biotechnology, The University of Suwon, Hwaseong 18323, Gyeonggi-do, Republic of Korea"},{"name":"College of Life Sciences, Linyi University, Linyi 276005, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Difan","family":"Deng","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences and Food Engineering, Liaocheng University, Liaocheng 252059, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yupeng","family":"Yin","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences and Food Engineering, Liaocheng University, Liaocheng 252059, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongmei","family":"Xi","sequence":"additional","affiliation":[{"name":"College of Life Sciences, Linyi University, Linyi 276005, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Phumbum","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, The University of Suwon, Hwaseong 18323, Gyeonggi-do, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Gao","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences and Food Engineering, Liaocheng University, Liaocheng 252059, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-3117-7553","authenticated-orcid":false,"given":"Rui","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, The University of Suwon, Hwaseong 18323, Gyeonggi-do, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0235-5281","authenticated-orcid":false,"given":"Kang","family":"Lei","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences and Food Engineering, Liaocheng University, Liaocheng 252059, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"18806","DOI":"10.1021\/acs.langmuir.4c01842","article-title":"Nanomaterials and Nano-technology in Agricultural Pesticide Delivery: A Review","volume":"40","author":"Jiang","year":"2024","journal-title":"Langmuir"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Zhang, B., Lv, F., and Yang, J. (2024). Pesticides Toxicity, Removal and Detoxification in Plants: A Review. Agronomy, 14.","DOI":"10.3390\/agronomy14061260"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Giugliano, R., Armenio, V., Savio, V., Vaccaro, E., Ciccotelli, V., and Vivaldi, B. (2024). Monitoring of Non-Maximum-Residue-Level Pesticides in Animal Feed: A Study from 2019 to 2023. Toxics, 12.","DOI":"10.3390\/toxics12090680"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"8913","DOI":"10.1021\/acs.jafc.2c03821","article-title":"Pesticide Research and Development: General Discussion and Spinosad Case","volume":"70","author":"Chio","year":"2022","journal-title":"J. Agric. Food Chem."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1002\/ps.3256","article-title":"A Perspective on the Role of Quantitative Structure\u2013Activity and Structure\u2013Property Relationships in Herbicide Discovery","volume":"68","author":"Clark","year":"2012","journal-title":"Pest Manag. Sci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"11075","DOI":"10.1021\/acs.jafc.1c07910","article-title":"A Competitive Edge: Competitor Inspired Scaffold Hopping in Herbicide Lead Optimization","volume":"70","author":"Barber","year":"2022","journal-title":"J. Agric. Food Chem."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"7079","DOI":"10.1021\/cr4005605","article-title":"Application of the Intermediate Derivatization Approach in Agrochemical Discovery","volume":"114","author":"Guan","year":"2014","journal-title":"Chem. Rev."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"494","DOI":"10.1002\/ps.2300","article-title":"Physionomics and Metabolomics\u2013Two Key Approaches in Herbicidal Mode of Action Discovery","volume":"68","author":"Grossmann","year":"2012","journal-title":"Pest Manag. Sci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1075","DOI":"10.1021\/acs.jafc.4c08092","article-title":"Pyruvate Kinase-Based Novel 2-Thiazol-2-yl-1,3,4-oxadiazoles Discovery as Fungicidal Highly Active Leads","volume":"73","author":"Gao","year":"2025","journal-title":"J. Agric. Food Chem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1475","DOI":"10.1016\/j.ijbiomac.2020.07.237","article-title":"Direct Label-Free Methods for Identification of Target Proteins in Agrochemicals","volume":"164","author":"Zhao","year":"2020","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1126\/science.1233606","article-title":"Monitoring drug target engagement in cells and tissues using the cellular thermal shift assay","volume":"341","author":"Molina","year":"2013","journal-title":"Science"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1146\/annurev-pharmtox-010715-103715","article-title":"The cellular thermal shift assay: A novel biophysical assay for in situ drug target engagement and mechanistic biomarker studies","volume":"56","author":"Martinez","year":"2016","journal-title":"Annu. Rev. Pharmacol."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Savitski, M.M., Reinhard, F.B.M., Franken, H., Werner, T., Savitski, M.F., Eberhard, D., Molina, D.M., Jafari, R., Dovega, R.B., and Klaeger, S. (2014). Tracking cancer drugs in living cells by thermal profiling of the proteome. Science, 346.","DOI":"10.1126\/science.1255784"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1038\/nature13264","article-title":"The metabolite \u03b1-ketoglutarate extends lifespan by inhibiting ATP synthase and TOR","volume":"510","author":"Chin","year":"2014","journal-title":"Nature"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"9078","DOI":"10.1073\/pnas.1000148107","article-title":"Quantitative proteomics approach for identifying protein-drug interactions in complex mixtures using protein stability measurements","volume":"107","author":"West","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"M111.016642-1","DOI":"10.1074\/mcp.M111.016642","article-title":"Target identification by chromatographic co-elution: Monitoring of drug-protein interactions without immobilization or chemical derivatization","volume":"11","author":"Chan","year":"2012","journal-title":"Mol. Cell. Proteom."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"\u0160kerlov\u00e1, J., Berndtsson, J., Nolte, H., Ott, M., and Stenmark, P. (2021). Structure of the native pyruvate dehydrogenase complex reveals the mechanism of substrate insertion. Nat. Commun., 12.","DOI":"10.1038\/s41467-021-25570-y"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1608","DOI":"10.1016\/j.bbapap.2014.06.003","article-title":"Structure and functioning mechanism of transketolase","volume":"1844","author":"Kochetov","year":"2014","journal-title":"BBA-Proteins Proteom."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1016\/S1096-4959(03)00081-2","article-title":"Pyruvate kinase: Current status of regulatory and functional properties","volume":"135","author":"Ponce","year":"2003","journal-title":"Comp. Biochem. Physiol. B Biochem. Mol. Biol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1016\/j.abb.2017.06.019","article-title":"The dihydroorotate dehydrogenases: Past and present","volume":"632","author":"Reis","year":"2017","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1002\/(SICI)1096-9063(199812)54:4<327::AID-PS828>3.0.CO;2-C","article-title":"High-throughput screening as a tool for agrochemical discovery: Automated synthesis, compound input, assay design and process management","volume":"54","author":"Ridley","year":"1998","journal-title":"Pestic. Sci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1924","DOI":"10.1016\/j.bmcl.2007.01.038","article-title":"Synthesis and antibacterial activity of 4,5,6,7-tetrahydro-thieno[3,2-c]pyridine quinolones","volume":"17","author":"Srivastava","year":"2007","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Moloney, G.P. (2001). Methyl 3-Hydroxythieno[2,3-b]pyridine-2-carboxylate. Molecules, 6.","DOI":"10.3390\/M203"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"77","DOI":"10.3998\/ark.5550190.0009.e09","article-title":"Synthesis of new 4-(phenylamino)thieno[2,3-b]pyridines and derivatives of the novel benzo[b]thieno[3,2-h]-1,6-naphthyridine tetracyclic system","volume":"14","author":"Pinheiro","year":"2008","journal-title":"Arkivoc"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"965","DOI":"10.4155\/fmc-2017-0049","article-title":"Design, synthesis and multitarget biological profiling of second-generation anti-Alzheimer rhein\u2013huprine hybrids","volume":"9","author":"Betari","year":"2017","journal-title":"Future Med. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Lodha, K.K., Wavhal, D.S., Bhalekar, S.B., Meshram, R.J., and Shinde, V.S. (2022). Exploring new tetrahydrothienopyridine derivatives as platelet agglutination inhibitors: Synthesis, biological evaluation and in silico study. ChemistrySelect, 7.","DOI":"10.1002\/slct.202103428"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"6087","DOI":"10.1016\/j.tetlet.2013.08.135","article-title":"Efficient \u2018one-pot\u2019 methodology for the synthesis of novel tetrahydro-\u03b2-carboline, tetrahydroisoquinoline and tetrahydrothienopyridine derivatives","volume":"54","author":"Ionescu","year":"2013","journal-title":"Tetrahedron Lett."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Rossetti, A., Bono, N., Candiani, G., Meneghetti, F., Roda, G., and Sacchetti, A. (2019). Synthesis and antimicrobial evaluation of novel chiral 2-amino-4,5,6,7-tetrahydrothieno[2,3-c]pyridine derivatives. Chem. Biodivers., 16.","DOI":"10.1002\/cbdv.201900097"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"988","DOI":"10.2174\/1389557514666141106131425","article-title":"Synthesis and biological activity of substituted-4,5,6,7-tetrahydrothieno pyridines: A review","volume":"14","author":"Sangshetti","year":"2014","journal-title":"Mini-Rev. Med. Chem."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Wang, S., Liu, H., Wang, X., Lei, K., Li, G., Li, X., Wei, L., and Quan, Z. (2019). Synthesis and evaluation of anticonvulsant activities of 7-phenyl-4,5,6,7-tetrahydrothieno[3,2-b]pyridine derivatives. Arch. Pharm. Chem. Life Sci., 352.","DOI":"10.1002\/ardp.201900106"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Wang, S., Liu, H., Wang, X., Lei, K., Li, G., and Quan, Z. (2019). Synthesis and evaluation of antidepressant activities of 5-aryl-4,5-dihydrotetrazolo[1,5-a]thieno[2,3-e]pyridine derivatives. Molecules, 24.","DOI":"10.3390\/molecules24101857"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1054","DOI":"10.1002\/ps.4029","article-title":"Azole fungicides\u2014Understanding resistance mechanisms in agricultural fungal pathogens","volume":"71","author":"Price","year":"2015","journal-title":"Pest Manag. Sci."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1007","DOI":"10.1002\/ps.873","article-title":"Synthesis and fungicidal activity of ethaboxam against Oomycetes","volume":"60","author":"Kim","year":"2004","journal-title":"Pest Manag. Sci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2696","DOI":"10.1094\/PDIS-10-19-2253-RE","article-title":"Activity of the succinate dehydrogenase inhibitor fungicide penthiopyrad against Sclerotinia sclerotiorum","volume":"104","author":"Mao","year":"2020","journal-title":"Plant Dis."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1016\/j.pestbp.2019.07.012","article-title":"Stereoselective bioactivity of the chiral triazole fungicide prothioconazole and its metabolite","volume":"160","author":"Zhang","year":"2019","journal-title":"Pestic. Biochem. Physiol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1007\/s00294-014-0438-x","article-title":"Identification and functional analysis of AG1-IA specific genes of Rhizoctonia solani","volume":"60","author":"Ghosh","year":"2014","journal-title":"Curr. Genet."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"4253","DOI":"10.1021\/acs.jafc.1c00132","article-title":"Discovery of novel 3,4-dichloroisothiazole-containing coumarins as fungicidal leads","volume":"69","author":"Lv","year":"2021","journal-title":"J. Agric. Food Chem."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"14125","DOI":"10.1021\/acs.jafc.3c02444","article-title":"CoMFA directed molecular design for significantly improving fungicidal activity of novel [1,2,4]-triazolo-[3,4-b][1,3,4]-thiadiazoles","volume":"71","author":"Gao","year":"2023","journal-title":"J. Agric. Food Chem."}],"container-title":["Microorganisms"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-2607\/13\/7\/1588\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:05:10Z","timestamp":1760033110000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-2607\/13\/7\/1588"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,5]]},"references-count":38,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2025,7]]}},"alternative-id":["microorganisms13071588"],"URL":"https:\/\/doi.org\/10.3390\/microorganisms13071588","relation":{},"ISSN":["2076-2607"],"issn-type":[{"value":"2076-2607","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,7,5]]}}}