{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T17:53:43Z","timestamp":1791222823408,"version":"4.1.0"},"reference-count":50,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2025,6,24]],"date-time":"2025-06-24T00:00:00Z","timestamp":1750723200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100018818","name":"National Research, Development, and Innovation Office","doi-asserted-by":"publisher","award":["NKKP-ADVANCED 149447"],"award-info":[{"award-number":["NKKP-ADVANCED 149447"]}],"id":[{"id":"10.13039\/501100018818","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100018818","name":"National Research, Development, and Innovation Office","doi-asserted-by":"publisher","award":["RRF 2.3.1-21-2022-00015"],"award-info":[{"award-number":["RRF 2.3.1-21-2022-00015"]}],"id":[{"id":"10.13039\/501100018818","id-type":"DOI","asserted-by":"publisher"}]},{"name":"European Union","award":["NKKP-ADVANCED 149447"],"award-info":[{"award-number":["NKKP-ADVANCED 149447"]}]},{"name":"European Union","award":["RRF 2.3.1-21-2022-00015"],"award-info":[{"award-number":["RRF 2.3.1-21-2022-00015"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background: \u03b1-Hydroxyphosphonates, one of the most prominent classes of phosphonates, remain of utmost importance because of their potential and real biological activity as pharmaceutical or pesticide agents. The effect is the consequence of their enzyme inhibitory properties. Objectives: It was planned to make available new heterocyclic hydroxyphosphonate derivatives with cytotoxic activity. Methods: After optimizing the synthesis, 23 members of a new family, \u03b1-hydroxy-\u03b1-(benzothiophen-2-yl)-methylphosphonates, were prepared by the Pudovik reaction of benzo[b]thiophene-2-carboxaldehydes and diethyl phosphite. The addition was performed at 26 \u00b0C in the presence of triethylamine as the catalyst. One of the products was also characterized by single-crystal X-ray analysis. Results: The cytotoxic effect of the \u03b1-hydroxy-\u03b1-benzothiophenyl-methylphosphonates was tested on U266 myeloma, A2058 melanoma, HT-29 colon, and EBC-1 lung cancer cell lines. Most of the molecules showed significant activity; the greatest effects were seen after treatment with hydroxyphosphonates with a trifluoromethyl group in the benzene ring. Conclusions: The cytotoxic activity of the newly synthesized \u03b1-hydroxyphosphonates is encouraging to find even better derivatives.<\/jats:p>","DOI":"10.3390\/ph18070949","type":"journal-article","created":{"date-parts":[[2025,6,24]],"date-time":"2025-06-24T10:44:41Z","timestamp":1750761881000},"page":"949","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Synthesis and Cytotoxic Activity of a New Family of \u03b1-Hydroxyphosphonates with the Benzothiophene Scaffold"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3538-8872","authenticated-orcid":false,"given":"M\u00e1ty\u00e1s","family":"Milen","sequence":"first","affiliation":[{"name":"Directorate of Drug Substance Development, Egis Pharmaceuticals Plc., P.O. Box 100, 1475 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tam\u00e1s Mikl\u00f3s","family":"John","sequence":"additional","affiliation":[{"name":"Directorate of Drug Substance Development, Egis Pharmaceuticals Plc., P.O. Box 100, 1475 Budapest, Hungary"},{"name":"Department of Organic Chemistry and Technology, Faculty of Chemical Technology and Biotechnology, Budapest University of Technology and Economics, M\u0171egyetem rkp. 3, 1111 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-6115-3185","authenticated-orcid":false,"given":"Anna S\u00e1ra","family":"Kis","sequence":"additional","affiliation":[{"name":"Department of Organic Chemistry and Technology, Faculty of Chemical Technology and Biotechnology, Budapest University of Technology and Economics, M\u0171egyetem rkp. 3, 1111 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0152-2746","authenticated-orcid":false,"given":"Zs\u00f3fia","family":"Gar\u00e1di","sequence":"additional","affiliation":[{"name":"Directorate of Drug Substance Development, Egis Pharmaceuticals Plc., P.O. Box 100, 1475 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-3559-6011","authenticated-orcid":false,"given":"Zsuzsanna","family":"Szalai","sequence":"additional","affiliation":[{"name":"Department of Organic Chemistry and Technology, Faculty of Chemical Technology and Biotechnology, Budapest University of Technology and Economics, M\u0171egyetem rkp. 3, 1111 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8912-8216","authenticated-orcid":false,"given":"Ang\u00e9la","family":"Tak\u00e1cs","sequence":"additional","affiliation":[{"name":"Institute of Genetics, Cell and Immunobiology, Semmelweis University, Nagyv\u00e1rad t\u00e9r 4, 1089 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L\u00e1szl\u00f3","family":"K\u0151hidai","sequence":"additional","affiliation":[{"name":"Institute of Genetics, Cell and Immunobiology, Semmelweis University, Nagyv\u00e1rad t\u00e9r 4, 1089 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8855-730X","authenticated-orcid":false,"given":"Konstantin","family":"Karaghiosoff","sequence":"additional","affiliation":[{"name":"Department Chemie, Ludwig-Maximilians-Universit\u00e4t M\u00fcnchen, Butenandtstr. 5-13, D-81377 M\u00fcnchen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5366-472X","authenticated-orcid":false,"given":"Gy\u00f6rgy","family":"Keglevich","sequence":"additional","affiliation":[{"name":"Department of Organic Chemistry and Technology, Faculty of Chemical Technology and Biotechnology, Budapest University of Technology and Economics, M\u0171egyetem rkp. 3, 1111 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,6,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1134","DOI":"10.1080\/10426500701578522","article-title":"Synthesis and biological activity of novel phosphonate derivatives containing of pyridyl and 1,2,3-triazole rings","volume":"183","author":"Chen","year":"2008","journal-title":"Phosphorus Sulfur Silicon Relat. Elem."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1070\/RC2006v075n03ABEH001193","article-title":"Chiral hydroxyl phosphonates: Synthesis, configuration and biological properties","volume":"75","author":"Kolodiazhnyi","year":"2006","journal-title":"Russ. Chem. Rev."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2020","DOI":"10.1002\/cjoc.201090337","article-title":"Synthesis and Herbicidal Activity of \u03b1-Hydroxy Phosphonate Derivatives Containing Pyrimidine Moiety","volume":"28","author":"Song","year":"2010","journal-title":"Chin. J. Chem."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1362","DOI":"10.1080\/10426507.2016.1206103","article-title":"Synthesis and insecticidal activities of O,O-dialkyl-2-[3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carbonyloxy] (aryl)methylphosphonates","volume":"191","author":"Wang","year":"2016","journal-title":"Phosphorus Sulfur Silicon Relat. Elem."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2554","DOI":"10.1021\/ja01614a061","article-title":"The New Insecticide O,O-Dimethyl 2,2,2-Trichloro-1-hydroxyethylphosphonate","volume":"77","author":"Lorenz","year":"1955","journal-title":"J. Am. Chem. Soc."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/j.jfluchem.2016.11.008","article-title":"Synthesis and herbicidal activity of \u03b1-[(substituted phenoxybutyryloxy or valeryoxy)]alkylphosphonatesand 2-(substituted phenoxybutyryloxy)alkyl-5,5-dimethyl-1,3,2-dioxaphosphinan-2-one containing fluorine","volume":"193","author":"Wang","year":"2017","journal-title":"J. Fluor. Chem."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"196","DOI":"10.3998\/ark.5550190.0007.b20","article-title":"Synthesis and antibacterial activities of \u03b1-hydroxyphosphonates and \u03b1-acetyloxyphosphonates derived from 2-chloroquinoline-3-carbaldehyde","volume":"11","author":"Pokalwar","year":"2006","journal-title":"Arkivoc"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1128","DOI":"10.1016\/j.ejmech.2009.12.013","article-title":"Synthesis, in vitro antibacterial and antifungal evaluations of new \u03b1-hydroxyphosphonate and new \u03b1-acetoxyphosphonate derivatives of tetrazolo [1,5-a] quinoline","volume":"45","author":"Kategaonkar","year":"2010","journal-title":"Eur. J. Med. Chem."},{"key":"ref_9","first-page":"2208","article-title":"Synthesis, spectral characterization and antimicrobial activity of \u03b1-hydroxyphosphonates","volume":"4","author":"Reddy","year":"2012","journal-title":"Pharma Chem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1080\/10426507.2015.1032412","article-title":"An efficient synthesis, spectral characterization, antimicrobial, and antioxidant activities of novel \u03b1-hydroxyphosphonates and \u03b1-hydroxyphosphinates","volume":"191","author":"Sampath","year":"2016","journal-title":"Phosphorus Sulfur Silicon Relat. Elem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"490","DOI":"10.1016\/j.ejmech.2014.06.053","article-title":"Synthesis and biological evaluation of novel N-aryl maleimide derivatives clubbed with \u03b1-hydroxyphosphonates","volume":"83","author":"Patil","year":"2014","journal-title":"Eur. J. Med. Chem."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"3343","DOI":"10.5012\/bkcs.2011.32.9.3343","article-title":"Neat Synthesis and Antioxidant Activity of \u03b1-Hydroxyphosphonates","volume":"32","author":"Rao","year":"2011","journal-title":"Bull. Korean Chem. Soc."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"957","DOI":"10.1002\/ardp.201200192","article-title":"Synthesis of \u03b1-Hydroxyphosphonates and Their Antioxidant Properties","volume":"345","author":"Naidu","year":"2012","journal-title":"Arch. Pharm. Chem. Life Sci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2566","DOI":"10.6023\/cjoc201406026","article-title":"Microwave-assisted synthesis and antitumor activity of salicyl acyloxy phosphonate derivatives","volume":"34","author":"Yang","year":"2014","journal-title":"Chin. J. Org. Chem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1611","DOI":"10.2174\/1389557518666180801110342","article-title":"Farnesyl Transferase Inhibitors as Potential Anticancer Agents","volume":"18","author":"Bagchi","year":"2018","journal-title":"Mini-Rev. Med. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1211","DOI":"10.2217\/fon.10.83","article-title":"Forodesine: Review of Preclinical and Clinical Data","volume":"6","author":"Gandhi","year":"2010","journal-title":"Future Oncol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2495","DOI":"10.1016\/S0968-0896(98)80023-0","article-title":"Synthesis of 1,1-difluoro-5-(1H-9-purinyl)-2-pentenylphosphonic acids and the related methano analogues. Remarkable effect of the nucleobases and the cyclopropane rings on inhibitory activity toward purine nucleoside phosphorylase","volume":"6","author":"Yokomatsu","year":"1998","journal-title":"Bioorg. Med. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"3916","DOI":"10.1039\/C5NJ00312A","article-title":"Phospho sulfonic acid: An efficient and recyclable solid acid catalyst for the solvent-free synthesis of \u03b1-hydroxyphosphonates and their anticancer properties","volume":"39","author":"Kalla","year":"2015","journal-title":"New J. Chem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"4557","DOI":"10.1021\/jm00022a022","article-title":"\u03b1-Hydroxy Phosphinyl-Based Inhibitors of Human Renin","volume":"38","author":"Patel","year":"1995","journal-title":"J. Med. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"6625","DOI":"10.1016\/S0040-4039(00)61002-X","article-title":"New hybrid transition state analog inhibitors of HIV protease with peripheric C2-symmetry","volume":"33","author":"Stowasser","year":"1992","journal-title":"Tetrahedron Lett."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"6317","DOI":"10.1016\/j.bmcl.2013.09.070","article-title":"Design, synthesis, and bioevaluation of viral 3C and 3C-like protease inhibitors","volume":"23","author":"Prior","year":"2013","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"3800","DOI":"10.1021\/bi00130a010","article-title":"Steady-state kinetic mechanism of ras farnesyl:protein transferase","volume":"31","author":"Pompliano","year":"1992","journal-title":"Biochemistry"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2169","DOI":"10.1016\/S0960-894X(97)00390-9","article-title":"Novel hydroxyphosphonate inhibitors of CD-45 tyrosine phosphatase","volume":"7","author":"Frechette","year":"1997","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2205","DOI":"10.1002\/cmdc.201600343","article-title":"Isoprenoid Biosynthesis Inhibitors Targeting Bacterial Cell Growth","volume":"11","author":"Desai","year":"2016","journal-title":"Chem. Med. Chem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"3193","DOI":"10.1021\/jf800029t","article-title":"Tailoring the Structure of Aminobisphosphonates To Target Plant P5C Reductase","volume":"56","author":"Forlani","year":"2008","journal-title":"J. Agric. Food Chem."},{"key":"ref_26","first-page":"932","article-title":"New synthesis of esters of phosphonic and thiophosphonic acids. XIII. Addition of diethyl thiophosphite to ketones and aldehydes","volume":"1952","author":"Pudovik","year":"1952","journal-title":"Izv. Akad. Nauk. SSSR Ser. Khim."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1055\/s-1979-28566","article-title":"Addition reactions of esters of phosphorus(III) acids with unsaturated systems","volume":"2","author":"Pudovik","year":"1979","journal-title":"Synthesis"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"R\u00e1dai, Z., and Keglevich, G. (2018). Synthesis and Reactions of \u03b1-Hydroxyphosphonates. Molecules, 23.","DOI":"10.3390\/molecules23061493"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1002\/hc.20649","article-title":"Microwave-Assisted Synthesis of \u03b1-Hydroxybenzylphosphonates and -benzylphosphine Oxides","volume":"22","author":"Keglevich","year":"2011","journal-title":"Heteroat. Chem."},{"key":"ref_30","first-page":"25","article-title":"Synthesis of 1-Hydroxyalkanephosphonic Esters on Alumina","volume":"916","author":"Foucaud","year":"1982","journal-title":"Synthesis"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1515\/gps-2016-0125","article-title":"To date the greenest method for the preparation of \u03b1-hydroxyphosphonates from substituted benzaldehydes and dialkyl phosphites","volume":"6","author":"Keglevich","year":"2017","journal-title":"Green. Process Synth."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1002","DOI":"10.1016\/j.ejmech.2017.07.038","article-title":"An overview of benzo[b]thiophene-based medicinal chemistry","volume":"138","author":"Keri","year":"2017","journal-title":"Eur. J. Med. Chem."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"379","DOI":"10.2165\/00003495-200060020-00013","article-title":"Raloxifene: A review of its use in postmenopausal osteoporosis","volume":"60","author":"Clemett","year":"2000","journal-title":"Drugs"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"858","DOI":"10.1177\/106002809603000725","article-title":"Zileuton: The first 5-lipoxygenase inhibitor for the treatment of asthma","volume":"30","author":"Wenzel","year":"1996","journal-title":"Ann. Pharmacother."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"339","DOI":"10.2165\/00003495-200969030-00009","article-title":"Sertaconazole: A review of its use in the management of superficial mycoses in dermatology and gynaecology","volume":"63","author":"Croxtall","year":"2009","journal-title":"Drugs"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Eldehna, W.M., Al-Ansary, G.H., Al-Warhi, T., Jaballah, M.Y., Elaasser, M., and Rashed, M. (2024). Identification of novel ureido benzothiophenes as dual VEGFR-2\/EGFR anticancer agents. Bioorg. Chem., 143.","DOI":"10.1016\/j.bioorg.2023.107037"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1073","DOI":"10.1039\/c3md00130j","article-title":"Synthesis and evaluation of a series of benzothiophene acrylonitrile analogs as anticancer agents","volume":"4","author":"Penthala","year":"2013","journal-title":"Med. Chem. Commun."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Mostafa, N., Chen, P.-J., Darwish, S.S., Su, Y.-C., Shiao, M.-H., Piazza, G.A., Abadi, A.H., Engel, M., and Abdel-Halim, M. (2024). N-Benzylated 5-hydroxybenzothiophene-2-carboxamides as multi-targeted Clk\/Dyrk inhibitors and potential anticancer agents. Cancers, 16.","DOI":"10.3390\/cancers16112033"},{"key":"ref_39","unstructured":"(DIAMOND, 2014). DIAMOND, version 3.2i."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"3266","DOI":"10.1021\/ja1001482","article-title":"Superelectrophiles and the effects of trifluoromethyl substituents","volume":"132","author":"Boblak","year":"2010","journal-title":"J. Am. Chem. Soc."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Nair, A.S., Singh, A.K., Kumar, A., Kumar, S., Sukumaran, S., Koyiparambath, V.P., Pappachen, L.K., Rangarajan, T.M., Kim, H., and Mathew, B. (2022). FDA-Approved Trifluoromethyl Group-Containing Drugs: A Review of 20 Years. Processes, 10.","DOI":"10.3390\/pr10102054"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"18856","DOI":"10.1039\/D4RA02856B","article-title":"Exploring the impact of trifluoromethyl (-CF3) functional group on the anti-cancer activity of isoxazole-based molecules: Design, synthesis, biological evaluation and molecular docking analysis","volume":"14","author":"Pattanayak","year":"2024","journal-title":"RSC Adv."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2251","DOI":"10.1016\/j.bmc.2004.02.007","article-title":"C17,20-Lyase inhibitors I. Structure-based de novo design and SAR study of C17,20-lyase inhibitors","volume":"12","author":"Matsunaga","year":"2004","journal-title":"Bioorg. Med. Chem."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.bmcl.2016.11.050","article-title":"A benzo[b]thiophene-based selective type 4 S1P receptor agonist","volume":"27","author":"Hur","year":"2017","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1021\/acs.oprd.8b00247","article-title":"Catalytic Deprotonative \u03b1-Formylation of Heteroarenes by an Amide Base Generated in Situ from Tetramethylammonium Fluoride and Tris(trimethylsilyl)amine","volume":"23","author":"Shigeno","year":"2019","journal-title":"Org. Process. Res. Dev."},{"key":"ref_46","unstructured":"(2020). Program Package \u2018CrysAlisPro 1.171.40.82a\u2019, Rigaku Oxford Diffraction."},{"key":"ref_47","unstructured":"Sheldrick, G.M. (1997). SHELXS-97: Program for Crystal Structure Solution, University of G\u00f6ttingen."},{"key":"ref_48","unstructured":"Sheldrick, G.M. (1997). SHELXL-97: Program for the Refinement of Crystal Structures, University of G\u00f6ttingen."},{"key":"ref_49","unstructured":"Spek, A.L. (1999). PLATON: A Multipurpose Crystallographic Tool, Utrecht University."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Szalai, Z., Bedn\u00e1rik, J., T\u00f3th, B.S., Tak\u00e1cs, A., Tekula, S., K\u0151hidai, L., Karaghiosoff, K., Drahos, L., and Keglevich, G. (2025). Cytotoxic Activity of Bisphosphonic Derivatives Obtained by the Michaelis-Arbuzov or the Pudovik Reaction. Pharmaceuticals, 18.","DOI":"10.3390\/ph18010091"}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/18\/7\/949\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:57:32Z","timestamp":1760032652000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/18\/7\/949"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6,24]]},"references-count":50,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2025,7]]}},"alternative-id":["ph18070949"],"URL":"https:\/\/doi.org\/10.3390\/ph18070949","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,6,24]]}}}