{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T00:43:28Z","timestamp":1759970608447,"version":"build-2065373602"},"reference-count":48,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2025,1,23]],"date-time":"2025-01-23T00:00:00Z","timestamp":1737590400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>The thermal characterisation and toxicity profile of a class of disubstituted heterofused triazinones were revealed in this article for the first time. The thermal behaviour of molecules 1\u201312 was investigated by means of TG and DSC analyses performed in an air atmosphere and by the coupled TG\/FTIR technique in a nitrogen atmosphere. The heating atmosphere affects both the stability of compounds and the degradation mechanism. A two-step degradation occurs in air, while a one-step degradation takes place in nitrogen, both preceded by a melting process. Compound 3 shows the highest thermal stability, while molecule 10\u2014the lowest. The thermal decomposition of the studied heterocyclic molecules begins with the degradation of the bicyclic system, resulting in the formation of volatile gaseous products such as ammonia\/hydrazine, hydrogen cyanide, carbon dioxide, and isocyanates. In the further stage, mainly aromatic compounds are released, and their chemical composition depends on the presence and type of substituents at the phenyl and benzyl moieties. In addition, the toxicity profiles of molecules were assessed in the animal (zebrafish) and cellular (erythrocytes) models, and the antihaemolytic activity was evaluated in the AAPH- and H2O2-induced haemolysis inhibition assays. It was found that all the tested compounds are safe for the developing zebrafish and red blood cells, and they are able to effectively protect erythrocytes from oxidative damage. These favourable properties make them promising drug candidates suitable for further in vivo studies.<\/jats:p>","DOI":"10.3390\/molecules30030506","type":"journal-article","created":{"date-parts":[[2025,1,23]],"date-time":"2025-01-23T05:49:54Z","timestamp":1737611394000},"page":"506","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Thermal Characterisation and Toxicity Profile of Potential Drugs from a Class of Disubstituted Heterofused Triazinones"],"prefix":"10.3390","volume":"30","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1576-097X","authenticated-orcid":false,"given":"Ma\u0142gorzata","family":"Sztanke","sequence":"first","affiliation":[{"name":"Department of Medical Chemistry, Medical University of Lublin, 4A Chod\u017aki Street, 20-093 Lublin, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Renata","family":"\u0141yszczek","sequence":"additional","affiliation":[{"name":"Department of General and Coordination Chemistry and Crystallography, Institute of Chemical Sciences, Faculty of Chemistry, Maria Curie-Sk\u0142odowska University in Lublin, M.C. Sk\u0142odowskiej Sq. 2, 20-031 Lublin, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5397-4103","authenticated-orcid":false,"given":"Agnieszka","family":"Ostasz","sequence":"additional","affiliation":[{"name":"Department of General and Coordination Chemistry and Crystallography, Institute of Chemical Sciences, Faculty of Chemistry, Maria Curie-Sk\u0142odowska University in Lublin, M.C. Sk\u0142odowskiej Sq. 2, 20-031 Lublin, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Halina","family":"G\u0142uchowska","sequence":"additional","affiliation":[{"name":"Department of General and Coordination Chemistry and Crystallography, Institute of Chemical Sciences, Faculty of Chemistry, Maria Curie-Sk\u0142odowska University in Lublin, M.C. Sk\u0142odowskiej Sq. 2, 20-031 Lublin, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1898-5245","authenticated-orcid":false,"given":"Krzysztof","family":"Sztanke","sequence":"additional","affiliation":[{"name":"Laboratory of Bioorganic Compounds Synthesis and Analysis, Medical University of Lublin, 4A Chod\u017aki Street, 20-093 Lublin, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,1,23]]},"reference":[{"key":"ref_1","first-page":"71","article-title":"Synthesis of new derivatives of 3-benzyl-8-aryl-7,8-dihydro-6H-imidazo[2,1-c][1,2,4]triazin-4-one","volume":"54","author":"Sztanke","year":"1997","journal-title":"Acta Pol. Pharm. Drug Res."},{"key":"ref_2","unstructured":"Pasternak, K. (2009). Antiproliferative activity of new synthesized derivatives of imidazotriazinone in breast cancer cell line (T47D). Pierwiastki, \u015arodowisko i \u017bycie Cz\u0142owieka, Polskie Towarzystwo Magnezologiczne."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1016\/j.chroma.2013.09.060","article-title":"Reversed-phase liquid chromatography with octadecylsilyl, immobilized artificial membrane and cholesterol columns in correlation studies with in silico biological descriptors of newly synthesized antiproliferative and analgesic active compounds","volume":"1318","author":"Janicka","year":"2013","journal-title":"J. Chromatogr. A"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Janicka, M., Sztanke, M., and Sztanke, K. (2024). Modeling the Blood-Brain Barrier Permeability of Potential Heterocyclic Drugs via Biomimetic IAM Chromatography Technique Combined with QSAR Methodology. Molecules, 29.","DOI":"10.3390\/molecules29020287"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Sztanke, M., Sztanke, K., Ostasz, A., G\u0142uchowska, H., and \u0141yszczek, R. (2023). Thermal Investigations of Annelated Triazinones\u2014Potential Analgesic and Anticancer Agents. Molecules, 28.","DOI":"10.3390\/molecules28186542"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"17963","DOI":"10.1039\/C5TA05291B","article-title":"A high density pyrazolo-triazine explosive (PTX)","volume":"3","author":"Schulze","year":"2015","journal-title":"J. Mater. Chem. A"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1212","DOI":"10.1039\/D3NJ04391F","article-title":"Concise synthesis of a fused energetic pyrazolotriazine with good performance","volume":"48","author":"Shi","year":"2024","journal-title":"N. J. Chem."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"13874","DOI":"10.1039\/D2NJ02515A","article-title":"Detonation performance enhancement through a positional isomerism modification strategy","volume":"46","author":"Hu","year":"2022","journal-title":"N. J. Chem."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"4221","DOI":"10.1021\/acs.cgd.2c00237","article-title":"Studies on the Synthesis and Properties of High-Energy Low-Sensitivity Compounds Based on 3-Amino-1,2,4-triazole","volume":"22","author":"Yang","year":"2022","journal-title":"Cryst. Growth Des."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"15292","DOI":"10.1039\/D2DT02885A","article-title":"C\u2013C bonded bis-5,6 fused triazole\u2013triazine compound: An advanced heat-resistant explosive with high energy and low sensitivity","volume":"51","author":"Li","year":"2022","journal-title":"Dalton Trans."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1067","DOI":"10.1039\/D3NJ05248F","article-title":"Towards improved comprehensive energetic properties by skeleton modification","volume":"48","author":"Li","year":"2024","journal-title":"N. J. Chem."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1050","DOI":"10.1016\/j.matdes.2015.11.060","article-title":"Searching for long intra-annular nitrogen chains: Synthesis, characterization, and decomposition mechanism of tetrazolo[1,5-b][1,2,4]triazines","volume":"90","author":"Zhao","year":"2016","journal-title":"Mater. Des."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1208\/s12249-012-9916-y","article-title":"Thermal stability and decomposition kinetic studies of acyclovir and zidovudine drug compounds","volume":"14","author":"Shamsipur","year":"2013","journal-title":"AAPS PharmSciTech"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"638","DOI":"10.3109\/03639045.2010.534099","article-title":"Thermal behavior study and decomposition kinetics of amiodarone hydrochloride under isothermal conditions","volume":"37","author":"Yoshida","year":"2011","journal-title":"Drug Dev. Ind. Pharm."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1023\/A:1016015113795","article-title":"Applications of thermal analysis and coupled techniques in pharmaceutical industry","volume":"68","author":"Giron","year":"2002","journal-title":"J. Therm. Anal. Calorim."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1016\/j.ajps.2017.12.001","article-title":"Non-isothermal dehydration kinetic study of aspartame hemihydrate using DSC, TGA and DSC-FTIR microspectroscopy","volume":"13","author":"Hsieh","year":"2018","journal-title":"Asian J. Pharm. Sci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"127099","DOI":"10.1016\/j.molstruc.2019.127099","article-title":"DFT, spectroscopic, DSC\/TGA, electronic, biological and molecular docking investigation of 2,5-thiophenedicarboxylic acid: A promising anticancer agent","volume":"1200","author":"Ramalingam","year":"2020","journal-title":"J. Mol. Struct."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Alamro, F.S., Tolan, D.A., El-Nahas, A.M., Ahmed, H.A., El-Atawy, M.A., Al-Kadhi, N.S., Aziz, S.G., and Shibl, M.F. (2022). Wide nematogenic azomethine\/ester liquid crystals based on new biphenyl derivatives: Mesomorphic and computational studies. Molecules, 27.","DOI":"10.3390\/molecules27134150"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"105975","DOI":"10.1016\/j.est.2022.105975","article-title":"Experimental and numerical analysis of a phase change material-based shell-and-tube heat exchanger for cold thermal energy storage","volume":"56","author":"Fragnito","year":"2022","journal-title":"J. Energy Storage"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"119047","DOI":"10.1016\/j.applthermaleng.2022.119047","article-title":"Multi-objective optimization of a phase change material-based shell-and-tube heat exchanger for cold thermal energy storage: Experiments and numerical modeling","volume":"215","author":"Bianco","year":"2022","journal-title":"Appl. Therm. Eng."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1080\/05704929708003320","article-title":"Thermogravimetry\u2013Infrared Spectroscopy (TG-FTIR) Coupled Analysis","volume":"32","author":"Materazzi","year":"1997","journal-title":"Appl. Spectrosc. Rev."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Huynh-Ba, K. (2009). Impact of solid-state characteristics to the physical stability of drug substance and drug product. Handbook of Stability testing in Pharmaceutical Development, Springer.","DOI":"10.1007\/978-0-387-85627-8"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1007\/s10973-005-0779-2","article-title":"Characterization and quantification of amorphous content in some selected parenteral cephalosporins by calorimetric method","volume":"81","author":"Chadha","year":"2005","journal-title":"J. Therm. Anal. Calorim."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2389","DOI":"10.1039\/C4CE02563F","article-title":"Polymorphism and solid-to-solid phase transitions of a simple organic molecule, 3-chloroisonicotinic acid","volume":"17","author":"Long","year":"2015","journal-title":"CrystEngComm"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"234","DOI":"10.18433\/J3J30Z","article-title":"An insight into thermodynamic relationship between polymorphic forms of efavirenz","volume":"15","author":"Chadha","year":"2012","journal-title":"J. Pharm. Pharm. Sci."},{"key":"ref_26","unstructured":"Yoshioka, S., and Stella, V.J. (2002). Stability of Drugs and Dosage Forms, Kluwer Academic Publisher."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Sztanke, M., Rzymowska, J., and Sztanke, K. (2022). Anti-Tumor Active Isopropylated Fused Azaisocytosine-Containing Congeners Are Safe for Developing Danio rerio as well as Red Blood Cells and Activate Apoptotic Caspases in Human Breast Carcinoma Cells. Molecules, 27.","DOI":"10.3390\/molecules27041211"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1515\/revic-2021-0044","article-title":"Main group cyanides: From hydrogen cyanide to cyanido-complexes","volume":"43","author":"Schulz","year":"2023","journal-title":"Rev. Inorg. Chem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/j.jms.2008.01.006","article-title":"Near infrared emission spectrum of HCN","volume":"249","author":"Mellau","year":"2008","journal-title":"J. Mol. Spectrosc."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Krupa, J., Wierzejewska, M., and Lundell, J. (2023). Experimental FTIR-MI and Theoretical Studies of Isocyanic Acid Aggregates. Molecules, 28.","DOI":"10.3390\/molecules28031430"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"911","DOI":"10.1139\/v57-123","article-title":"The infrared and Raman spectra of toluene, toluene-\u03b1-d3, m-xylene, and m-xylene-\u03b1\u03b1\u2019-d6","volume":"35","author":"Wilmshurst","year":"1957","journal-title":"Can. J. Chem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1007\/s12648-012-0037-y","article-title":"Amine inversion effects on the IR spectra of aniline in the gas phase and cold inert gas matrixes","volume":"86","author":"Mukherjee","year":"2012","journal-title":"Indian J. Phys."},{"key":"ref_33","first-page":"92","article-title":"Synchrotron-based highest resolution FTIR spectroscopy of chlorobenzene","volume":"315","author":"Sieghard","year":"2015","journal-title":"J. Mol. Struc."},{"key":"ref_34","unstructured":"Silverstein, R.M., and Webster, F.X. (1996). Spectrometric Identification of Organic Compounds, Wiley. [6th ed.]."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1016\/j.molstruc.2017.07.053","article-title":"Improved assignments of the vibrational fundamental modes of ortho-, meta-, and para-xylene using gas- and liquid-phase infrared and Raman spectra combined with ab initio calculations: Quantitative gas phase infrared spectra for detection","volume":"1149","author":"Lindenmaier","year":"2017","journal-title":"J. Mol. Struct."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1023\/A:1010164709840","article-title":"Thermal Analysis of Manganese(II) Complexes With Glycine","volume":"63","author":"Mrozek","year":"2001","journal-title":"J. Therm. Anal. Calorim."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1038\/s44172-023-00105-z","article-title":"Gas phase multicomponent detection and analysis combining broadband dual-frequency comb absorption spectroscopy and deep learning","volume":"2","author":"Tian","year":"2023","journal-title":"Commun. Eng."},{"key":"ref_38","unstructured":"OECD (2013). OECD Guidelines for the Testing of Chemicals, Test No. 236: Fish Embryo Acute Toxicity (FET) Test, OECD."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Bauer, B., Mally, A., and Liedtke, D. (2021). Zebrafish Embryos and Larvae as Alternative Animal Models for Toxicity Testing. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms222413417"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1293\/tox.2020-0021","article-title":"Application of zebrafish to safety evaluation in drug discovery","volume":"33","author":"Miyawaki","year":"2020","journal-title":"Toxicol. Pathol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1016\/bs.ctdb.2016.10.007","article-title":"Zebrafish in toxicology and environmental health","volume":"124","author":"Bambino","year":"2017","journal-title":"Curr. Top. Dev. Biol."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Modarresi Chahardehi, A., Arsad, H., and Lim, V. (2020). Zebrafish as a Successful Animal Model for Screening Toxicity of Medicinal Plants. Plants, 9.","DOI":"10.3390\/plants9101345"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Rosa, J.G.S., Lima, C., and Lopes-Ferreira, M. (2022). Zebrafish Larvae Behavior Models as a Tool for Drug Screenings and Pre-Clinical Trials: A Review. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23126647"},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Lee, H.-C., Lin, C.-Y., and Tsai, H.-J. (2021). Zebrafish, an In Vivo Platform to Screen Drugs and Proteins for Biomedical Use. Pharmaceuticals, 14.","DOI":"10.3390\/ph14060500"},{"key":"ref_45","first-page":"388","article-title":"Probit analysis","volume":"78","author":"Finney","year":"1952","journal-title":"J. Inst. Actuar."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1002\/cbf.3135","article-title":"The use of erythrocyte fragility to assess xenobiotic cytotoxicity","volume":"33","author":"Pagano","year":"2015","journal-title":"Cell Biochem. Funct."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"S\u00e6b\u00f8, I.P., Bj\u00f8r\u00e5s, M., Franzyk, H., Helgesen, E., and Booth, J.A. (2023). Optimization of the hemolysis assay for the assessment of cytotoxicity. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24032914"},{"key":"ref_48","unstructured":"(2010). Directive 2010\/63\/EU of the European Parliament and of the Council of 22 September 2010 on the protection of animals used for scientific purposes. Off. J. Eur. Union, L276, 33\u201379."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/30\/3\/506\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T10:34:29Z","timestamp":1759919669000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/30\/3\/506"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,1,23]]},"references-count":48,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2025,2]]}},"alternative-id":["molecules30030506"],"URL":"https:\/\/doi.org\/10.3390\/molecules30030506","relation":{},"ISSN":["1420-3049"],"issn-type":[{"type":"electronic","value":"1420-3049"}],"subject":[],"published":{"date-parts":[[2025,1,23]]}}}