{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T05:00:20Z","timestamp":1785474020977,"version":"3.56.0"},"reference-count":45,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T00:00:00Z","timestamp":1785283200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100005643","name":"University of Lodz","doi-asserted-by":"crossref","award":["#3\/IDUB\/DOS\/2021"],"award-info":[{"award-number":["#3\/IDUB\/DOS\/2021"]}],"id":[{"id":"10.13039\/501100005643","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100005643","name":"University of Lodz","doi-asserted-by":"crossref","award":["#19\/IGB\/2024"],"award-info":[{"award-number":["#19\/IGB\/2024"]}],"id":[{"id":"10.13039\/501100005643","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100005643","name":"University of Lodz","doi-asserted-by":"crossref","award":["B2411000000038.01"],"award-info":[{"award-number":["B2411000000038.01"]}],"id":[{"id":"10.13039\/501100005643","id-type":"DOI","asserted-by":"crossref"}]},{"award":["#3\/IDUB\/DOS\/2021"],"award-info":[{"award-number":["#3\/IDUB\/DOS\/2021"]}],"id":[{"id":"https:\/\/ror.org\/05cq64r17","id-type":"ROR","asserted-by":"publisher"}]},{"award":["#19\/IGB\/2024"],"award-info":[{"award-number":["#19\/IGB\/2024"]}],"id":[{"id":"https:\/\/ror.org\/05cq64r17","id-type":"ROR","asserted-by":"publisher"}]},{"award":["B2411000000038.01"],"award-info":[{"award-number":["B2411000000038.01"]}],"id":[{"id":"https:\/\/ror.org\/05cq64r17","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005888","name":"Medical University of Lodz","doi-asserted-by":"crossref","award":["503\/1-156-02\/503-11-001"],"award-info":[{"award-number":["503\/1-156-02\/503-11-001"]}],"id":[{"id":"10.13039\/501100005888","id-type":"DOI","asserted-by":"crossref"}]},{"award":["503\/1-156-02\/503-11-001"],"award-info":[{"award-number":["503\/1-156-02\/503-11-001"]}],"id":[{"id":"https:\/\/ror.org\/02t4ekc95","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>The emergence of antifungal resistance highlights the need for new chemotypes with improved biological activity. In this study, a series of new 3-CF3-1,2,4-triazin-6(1H)-ones was synthesized via a (3+3)-cycloaddition of in situ-generated CF3-nitrile imines with amino acid esters, followed by DDQ-mediated chemoselective oxidation of the corresponding 4,5-dihydro intermediates. The compounds were evaluated for antifungal, antibacterial, and cytotoxic activities. The synthesized derivatives displayed selective antifungal activity, whereas only weak antibacterial and cytotoxic effects were observed. The highest potency was observed for C(5)-unsubstituted derivatives, which exhibited the broadest antimicrobial spectrum and inhibited the growth of Candida albicans, Trichophyton rubrum, and Epidermophyton floccosum with MIC50 values below 4 mg\/L. In addition, the dermatophytes showed a biphasic dose-dependent response, characterized by growth stimulation at low concentrations and inhibition at higher concentrations, consistent with hormesis. These findings identify trifluoromethylated 1,2,4-triazin-6(1H)-ones, particularly C(5)-unsubstituted derivatives, as promising scaffolds for the development of new antifungal agents.<\/jats:p>","DOI":"10.3390\/ijms27156796","type":"journal-article","created":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T11:45:14Z","timestamp":1785325514000},"page":"6796","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Design, Synthesis, and Biological Evaluation of Trifluoromethylated 1,2,4-Triazin-6-ones with Selective Antimycotic Activity and Hormesis Effects"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4775-2694","authenticated-orcid":false,"given":"Anna","family":"Kowalczyk","sequence":"first","affiliation":[{"name":"Department of Organic and Applied Chemistry, Faculty of Chemistry, University of Lodz, Tamka 12, 91-403 \u0141\u00f3d\u017a, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aleksandra","family":"Tr\u0119bska","sequence":"additional","affiliation":[{"name":"Department of Molecular Microbiology, Faculty of Biology and Environmental Protection, University of Lodz, Banacha 12\/16, 90-237 \u0141\u00f3d\u017a, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Milena","family":"S\u0119czkowska","sequence":"additional","affiliation":[{"name":"Department of Organic and Applied Chemistry, Faculty of Chemistry, University of Lodz, Tamka 12, 91-403 \u0141\u00f3d\u017a, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3129-4158","authenticated-orcid":false,"given":"Katarzyna","family":"Gach-Janczak","sequence":"additional","affiliation":[{"name":"Department of Biomolecular Chemistry, Medical University of Lodz, Mazowiecka 6\/8, 92-215 \u0141\u00f3d\u017a, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0172-0213","authenticated-orcid":false,"given":"Anita","family":"Ciesielska","sequence":"additional","affiliation":[{"name":"Department of Molecular Microbiology, Faculty of Biology and Environmental Protection, University of Lodz, Banacha 12\/16, 90-237 \u0141\u00f3d\u017a, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4416-8289","authenticated-orcid":false,"given":"Pawe\u0142","family":"St\u0105czek","sequence":"additional","affiliation":[{"name":"Department of Molecular Microbiology, Faculty of Biology and Environmental Protection, University of Lodz, Banacha 12\/16, 90-237 \u0141\u00f3d\u017a, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8789-9690","authenticated-orcid":false,"given":"Marcin","family":"Jasi\u0144ski","sequence":"additional","affiliation":[{"name":"Department of Organic and Applied Chemistry, Faculty of Chemistry, University of Lodz, Tamka 12, 91-403 \u0141\u00f3d\u017a, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e428","DOI":"10.1016\/S1473-3099(23)00692-8","article-title":"Global incidence and mortality of severe fungal disease","volume":"24","author":"Denning","year":"2024","journal-title":"Lancet Infect. Dis."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1146\/annurev-immunol-101220-034306","article-title":"Immunity to Invasive Fungal Diseases","volume":"40","author":"Casadevall","year":"2022","journal-title":"Annu. Rev. Immunol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1136\/ejhpharm-2020-002604","article-title":"Antifungal drug resistance: An update","volume":"29","author":"Denning","year":"2022","journal-title":"Eur. J. Hosp. Pharm."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"267","DOI":"10.7705\/biomedica.6943","article-title":"Disaster mycology","volume":"43","author":"Smith","year":"2023","journal-title":"Biomedica"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"72","DOI":"10.2174\/1389557513666140103111017","article-title":"1,2,3-Triazine scaffold as a potent biologically active moiety: A mini review","volume":"14","author":"Kumar","year":"2014","journal-title":"Mini Rev. Med. Chem."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"168","DOI":"10.2174\/1389557514666140131111837","article-title":"1,2,4-Triazine analogs as novel class of therapeutic agents","volume":"14","author":"Kumar","year":"2014","journal-title":"Mini Rev. Med. Chem."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"e00106-19","DOI":"10.1128\/AEM.00106-19","article-title":"Toxoflavin produced by Burkholderia gladioli from Lycoris aurea is a new broad-spectrum fungicide","volume":"85","author":"Li","year":"2019","journal-title":"Appl. Environ. Microbiol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"742","DOI":"10.1016\/j.bmcl.2009.11.048","article-title":"One pot synthesis and SAR of some novel 3-substituted 5,6-diphenyl-1,2,4-triazines as antifungal agents","volume":"20","author":"Sangshetti","year":"2010","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Li, L.-X., Jiao, J., Wang, X.-B., Chen, M., Fu, X.-C., Si, W.-J., and Yang, C.-L. (2018). Synthesis, characterization, and antifungal activity of novel benzo [4,5]imidazo [1,2-d][1,2,4]triazine derivatives. Molecules, 23.","DOI":"10.3390\/molecules23040746"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1016\/j.ejmech.2017.08.009","article-title":"An overview on the recent developments of 1,2,4-triazine derivatives as anticancer compounds","volume":"142","author":"Cascioferro","year":"2017","journal-title":"Eur. J. Med. Chem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1097\/CCO.0b013e3283388906","article-title":"Advances in radiotherapy of head and neck cancers","volume":"22","author":"Tao","year":"2010","journal-title":"Curr. Opin. Oncol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"5095","DOI":"10.1016\/j.bmcl.2009.07.036","article-title":"Crystal structure, antitumour and antimetastatic activities of disubstituted fused 1,2,4-triazinones","volume":"19","author":"Sztanke","year":"2009","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1816","DOI":"10.1016\/j.bmc.2010.01.053","article-title":"Synthesis and characterization of novel 1,2,4-triazine derivatives with antiproliferative activity","volume":"18","author":"Krauth","year":"2010","journal-title":"Bioorg. Med. Chem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1016\/j.ejmech.2018.07.003","article-title":"Design, synthesis and screening of 1, 2, 4-triazinone derivatives as potential antitumor agents with apoptosis inducing activity on MCF-7 breast cancer cell line","volume":"156","author":"Zaki","year":"2018","journal-title":"Eur. J. Med. Chem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"117634","DOI":"10.1016\/j.bmc.2024.117634","article-title":"1,3-Disubstituted-1,2,4-triazin-6-ones with potent activity against androgen receptor-dependent prostate cancer cells","volume":"101","author":"Zhao","year":"2024","journal-title":"Bioorg. Med. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2843","DOI":"10.1016\/j.tet.2019.04.005","article-title":"Synthesis of 3-perfluoroalkyl-substituted 1,2,4-triazinones through copper(I)-catalyzed interrupted click reaction","volume":"75","author":"Lin","year":"2019","journal-title":"Tetrahedron"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"3565","DOI":"10.1016\/j.bmc.2016.05.066","article-title":"Discovery of anti-cancer activity for benzo [1,2,4]triazin-7-ones: Very strong correlation to pleurotin and thioredoxin reductase inhibition","volume":"24","author":"Sweeney","year":"2016","journal-title":"Bioorg. Med. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1002\/ps.3765","article-title":"Synthesis and antifungal activity of 3-aryl-1,2,4-triazin-6-one derivatives","volume":"71","author":"Owen","year":"2015","journal-title":"Pest. Manag. Sci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2432","DOI":"10.1021\/cr4002879","article-title":"Fluor. in pharmaceutical industry: Fluor.-containing drugs introduced to the market in the last decade (2001\u20132011)","volume":"114","author":"Wang","year":"2014","journal-title":"Chem. Rev."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"e202400058","DOI":"10.1002\/hlca.202400058","article-title":"Advances in the synthesis of heterocycles with two and three heteroatoms using hydrazonoyl halides","volume":"107","author":"Yamaletdinova","year":"2024","journal-title":"Helv. Chim. Acta"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Mo, J., He, Y., and Gu, J. (2026). Research Progress in the cycloadditions of fluorinated nitrile imines. Synthesis.","DOI":"10.1055\/a-2888-9410"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"4462","DOI":"10.1021\/acs.orglett.3c01437","article-title":"One-pot synthesis of 1-aryl-3-trifluoromethylpyrazoles using nitrile imines and mercaptoacetaldehyde as a surrogate of acetylene","volume":"25","author":"Palusiak","year":"2023","journal-title":"Org. Lett."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1039\/D4MR00075G","article-title":"Trapping in situ generated CF3-nitrile imines with maleimides under solvent-free mechanochemical conditions","volume":"2","year":"2025","journal-title":"RSC Mechanochem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"3321","DOI":"10.1021\/acs.joc.5c03120","article-title":"Assembly of CF3-pyrazole-triazole hybrids through (3 + 3)-cycloaddition\/ring contraction and click chemistry","volume":"91","author":"Olszewska","year":"2026","journal-title":"J. Org. Chem."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Poper, W.K., \u015awi\u0105tek, K., Urbaniak, K., Olszewska, B., and Jasi\u0144ski, M. (2025). Lepidiline-derived imidazole-2(3H)-thiones: (3+2)-Cycloadditions vs. nucleophilic additions in reactions with fluorinated nitrile imines. Molecules, 30.","DOI":"10.3390\/molecules30193851"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"638","DOI":"10.1039\/D4OB01160K","article-title":"Synthesis of 3,5-(bis(fluoroalkyl)pyrazoles\/pyrazolines via [3 + 2]cycloaddition of di\/trifluoroacetohydrazonoyl bromides and trifluoromethyl-substituted alkenes","volume":"23","author":"Wang","year":"2025","journal-title":"Org. Biomol. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"134812","DOI":"10.1016\/j.tet.2025.134812","article-title":"[3+2]-Cycloaddition reactions of \u03b1-trifluoromethyl imino esters with nitrile imines: Construction of penta-substituted 5-CF3-1,2,4-triazolines","volume":"185","author":"Fan","year":"2025","journal-title":"Tetrahedron"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"5040","DOI":"10.1039\/D3OB00644A","article-title":"Regioselective [3 + 2] cycloaddition of di\/trifluoromethylated hydrazonoyl chlorides with fluorinated nitroalkenes: A facile access to 3-di\/trifluoroalkyl-5-fluoropyrazoles","volume":"21","author":"Zhang","year":"2023","journal-title":"Org. Biomol. Chem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"6600","DOI":"10.1039\/D5CC06713H","article-title":"Copper-catalysed decarboxylative alkynylation-cyclization reaction of propargylic cyclic carbonates with nitrile imines to access tetrasubstituted pyrazoles","volume":"62","author":"Yu","year":"2026","journal-title":"Chem. Commun."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"55106","DOI":"10.1039\/C7RA09766B","article-title":"1,3-Dipolar [3 + 3] cycloaddition of \u03b1-halohydroxamate-based azaoxyallyl cations with hydrazonoyl chloride-derived nitrile imines","volume":"7","author":"Zhao","year":"2017","journal-title":"RSC Adv."},{"key":"ref_31","first-page":"8","article-title":"Trapping of trifluoroacetonitrile imines with mercaptoacetaldehyde and mercaptocarboxylic acids: An access to fluorinated 1,3,4-thiadiazine derivatives via (3+3)-annulation","volume":"222\u2013223","author":"Michalak","year":"2019","journal-title":"J. Fluor. Chem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"10135","DOI":"10.1039\/C9CC05276C","article-title":"DABCO-Mediated [3+3] annulation of para-quinamines: Access to functionalized 1,2,4-triazinone derivatives","volume":"55","author":"Zhu","year":"2019","journal-title":"Chem. Commun."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2349","DOI":"10.1016\/j.tet.2015.03.015","article-title":"Tautomeric equilibrium in trifluoroacetaldehyde arylhydrazones","volume":"71","author":"Wojciechowska","year":"2015","journal-title":"Tetrahedron"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1016\/j.jfluchem.2017.07.014","article-title":"Expected and unexpected results in reactions of fluorinated nitrile imines with (cyclo)aliphatic thioketones","volume":"201","author":"Utecht","year":"2017","journal-title":"J. Fluor. Chem."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Kowalczyk, A., \u015awi\u0105tek, K., Celeda, M., Utecht-Jarzy\u0144ska, G., Jaskulska, A., Gach-Janczak, K., and Jasi\u0144ski, M. (2023). Trifluoromethylated 4,5-dihydro-1,2,4-triazin-6(1H)-ones via (3+3)-annulation of nitrile imines with a-amino esters. Materials, 16.","DOI":"10.3390\/ma16020856"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Bondy, S.C. (2023). The hormesis concept: Strengths and shortcomings. Biomolecules, 13.","DOI":"10.3390\/biom13101512"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"4561","DOI":"10.1021\/acs.jafc.1c01824","article-title":"Fungicide-induced hormesis in phytopathogenic fungi: A critical determinant of successful agriculture and environmental sustainability","volume":"69","author":"Agathokleous","year":"2021","journal-title":"J. Agric. Food Chem."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"108299","DOI":"10.1016\/j.soilbio.2021.108299","article-title":"Hormetic responses in arbuscular mycorrhizal fungi","volume":"159","author":"Jakobsen","year":"2021","journal-title":"Soil. Biol. Biochem."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1364","DOI":"10.1094\/PDIS-10-13-1059-RE","article-title":"Stimulatory effects of sublethal doses of dimethachlon on Sclerotinia sclerotiorum","volume":"98","author":"Zhou","year":"2014","journal-title":"Plant Dis."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Benedetto Tiz, D., D\u2019Al\u00ec, M., Iraci, N., Santi, C., and Sancineto, L. (2026). Halogen-containing drugs in 2025: A record year for the therapeutic use and synthesis of FDA-approved small molecules. Biomolecules, 16.","DOI":"10.3390\/biom16030381"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"861","DOI":"10.1080\/17568919.2026.2629538","article-title":"Key contemporary considerations for halogens in drug discovery","volume":"18","author":"Ali","year":"2026","journal-title":"Future Med. Chem."},{"key":"ref_42","unstructured":"Song, F., Bi, H., Jia, J., Du, G., Wang, S., Yang, N., and Li, H. (2021). Bromine-Containing Compounds as Antifungal Agents. (Patent CN112898227A)."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1016\/j.chemphyslip.2019.03.013","article-title":"ROS-induced lipid transformations without oxygen participation","volume":"221","author":"Shadyro","year":"2019","journal-title":"Chem. Phys. Lipids"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"2509","DOI":"10.1016\/j.bmc.2004.03.037","article-title":"Aminyl and iminyl radicals from arylhydrazones in the photo-induced DNA cleavage","volume":"12","author":"Hwu","year":"2004","journal-title":"Bioorg. Med. Chem."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/0022-1759(83)90303-4","article-title":"Rapid colorimetric assay for cellular growth and survival: Application to proliferation and cytotoxicity assays","volume":"65","author":"Mosmann","year":"1983","journal-title":"J. Immunol. Methods"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/15\/6796\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T04:39:38Z","timestamp":1785472778000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/15\/6796"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,29]]},"references-count":45,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["ijms27156796"],"URL":"https:\/\/doi.org\/10.3390\/ijms27156796","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,29]]}}}