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In this study, EX-3, a known trifluoromethyl oxadiazole (TFMO)-based HDAC inhibitor, was selected as a lead compound. Guided by its binding mode in Pseudomonas aeruginosa HDAC (Pa-HDAC), we designed and synthesized a series of TFMO-oxime ether derivatives. Most derivatives showed potent inhibitory activity against Pa-HDAC. Among them, compound 9q displayed the strongest enzyme inhibition with an IC50 value of 22.9 nM. The cocrystal complex structure of Pa-HDAC-9q revealed a ligand-induced conformational remodeling of Phe343 from a symmetry-related monomer, providing structural insight into the binding mechanism of this series. In greenhouse assays, compound 9b exhibited promising antifungal activity against southern corn rust and soybean rust, with EC50 values of 0.185 mg\/L and 0.462 mg\/L. These results identify TFMO-oxime ethers as promising scaffolds for HDAC-targeted fungicide discovery.<\/jats:p>","DOI":"10.1021\/acs.jafc.6c00599","type":"journal-article","created":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T06:02:07Z","timestamp":1787119327000},"page":"27247-27257","source":"Crossref","is-referenced-by-count":0,"title":["Structure-Based\nDiscovery of Trifluoromethyl Oxadiazole\nOxime Ethers as Potent Histone Deacetylase Inhibitors"],"prefix":"10.1021","volume":"74","author":[{"given":"Shuyu","family":"Dong","sequence":"first","affiliation":[{"name":"Central China Normal University , , ,","place":["Wuhan, PR China, 430079"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fang","family":"Qin","sequence":"additional","affiliation":[{"name":"Central China Normal University , , ,","place":["Wuhan, PR China, 430079"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zongwei","family":"Lu","sequence":"additional","affiliation":[{"name":"Central China Normal University , , ,","place":["Wuhan, PR China, 430079"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai","family":"Zhang","sequence":"additional","affiliation":[{"name":"Central China Normal University , , ,","place":["Wuhan, PR China, 430079"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yixuan","family":"Fu","sequence":"additional","affiliation":[{"name":"Central China Normal University , , ,","place":["Wuhan, PR China, 430079"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meiyun","family":"Peng","sequence":"additional","affiliation":[{"name":"Central China Normal University , , ,","place":["Wuhan, PR China, 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430079"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4384-2593","authenticated-orcid":true,"given":"Guangfu","family":"Yang","sequence":"additional","affiliation":[{"name":"Central China Normal University , , ,","place":["Wuhan, PR China, 430079"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,8,19]]},"reference":[{"key":"2026090311501406000_cit1","doi-asserted-by":"publisher","first-page":"4148","DOI":"10.1021\/jacsau.4c00828","article-title":"Slow-Binding and Covalent HDAC Inhibition: A New Paradigm?","volume":"4","author":"Raouf","year":"2024","journal-title":"JACS Au"},{"key":"2026090311501406000_cit2","doi-asserted-by":"publisher","first-page":"8315","DOI":"10.7150\/thno.45922","article-title":"Mitochondrial Sirtuin 3: New Emerging Biological Function and Therapeutic\nTarget","volume":"10","author":"Zhang","year":"2020","journal-title":"Theranostics"},{"key":"2026090311501406000_cit3","doi-asserted-by":"publisher","first-page":"731","DOI":"10.3390\/nu10060731","article-title":"Targeting\nHistone Deacetylases with\nNatural and Synthetic Agents: An Emerging Anticancer Strategy","volume":"10","author":"Singh","year":"2018","journal-title":"Nutrients"},{"key":"2026090311501406000_cit4","doi-asserted-by":"publisher","first-page":"115111","DOI":"10.1016\/j.bcp.2022.115111","article-title":"Zinc-Dependent\nHistone Deacetylases: Potential Therapeutic\nTargets for Arterial Hypertension","volume":"202","author":"Kee","year":"2022","journal-title":"Biochem.\nPharmacol."},{"key":"2026090311501406000_cit5","doi-asserted-by":"publisher","first-page":"104544","DOI":"10.1016\/j.drudis.2025.104544","article-title":"Choosing\nPan-HDAC or Selective HDAC\nInhibitors for Anticancer Therapy","volume":"30","author":"Ganai","year":"2025","journal-title":"Drug Discovery\nToday"},{"key":"2026090311501406000_cit6","doi-asserted-by":"publisher","first-page":"3971","DOI":"10.1093\/nar\/gkg473","article-title":"Histone Deacetylases\nin Fungi: Novel Members, New Facts","volume":"31","author":"Trojer","year":"2003","journal-title":"Nucleic\nAcids Res."},{"issue":"10","key":"2026090311501406000_cit7","doi-asserted-by":"publisher","first-page":"782","DOI":"10.1016\/j.fgb.2009.06.007","article-title":"HdaA, a\nclass 2 histone deacetylase of Aspergillus\nfumigatus, affects germination and secondary metabolite production","volume":"46","author":"Lee","year":"2009","journal-title":"Fungal Genet Biol."},{"key":"2026090311501406000_cit8","doi-asserted-by":"publisher","first-page":"96","DOI":"10.3389\/fmicb.2015.00096","article-title":"Histone\nDeacetylase Inhibition as\nan Alternative Strategy against Invasive Aspergillosis","volume":"6","author":"Lamoth","year":"2015","journal-title":"Front. 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