{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,21]],"date-time":"2025-11-21T05:27:15Z","timestamp":1763702835118,"version":"3.45.0"},"reference-count":59,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2025,11,19]],"date-time":"2025-11-19T00:00:00Z","timestamp":1763510400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006769","name":"Russian Science Foundation","doi-asserted-by":"crossref","award":["24-73-10151"],"award-info":[{"award-number":["24-73-10151"]}],"id":[{"id":"10.13039\/501100006769","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Pneumoconiosis Compensation Fund Board of Hong Kong","award":["9211315"],"award-info":[{"award-number":["9211315"]}]},{"DOI":"10.13039\/501100012190","name":"Ministry of Science and Higher Education of the Russian Federation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100012190","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Background: Malignant pleural mesothelioma (MPM) is an aggressive, asbestos-associated cancer characterized by dysregulated nitric oxide (NO) signaling and increased NO levels that facilitate tumor progression. Paradoxically, this aberrant NO environment creates a therapeutic vulnerability that can be exploited by NO-donor prodrugs, which overwhelm cellular defenses with cytotoxic concentrations of NO, inducing nitrosative stress and apoptosis. Within this framework, oxadiazole-based scaffolds have emerged as a promising platform for prodrug development owing to their versatile chemistry and potential as novel NO donors or synergistic agents. In our previous studies, we developed several series of hybrid architectures incorporating 1,2,5-oxadiazole 2-oxide (furoxan) and 1,2,4-oxadiazole scaffolds, producing compounds with diverse and tunable NO-donor activities. We further observed that the cytotoxicity of these hybrids was significantly influenced by the substituents introduced at position 3 of the furoxan ring. Methods: We designed and synthesized a series of bis(1,2,4-oxadiazolyl)furoxans to systematically investigate their NO-donating capacity, cytotoxicity against MPM cell lines, selectivity over healthy lung fibroblasts, and underlying anticancer mechanisms. Results: The bis(1,2,4-oxadiazolyl)furoxans exhibited lower overall cytotoxicity but significantly higher selectivity compared with previously studied 3-cyano-4-(1,2,4-oxadiazolyl)furoxans. Their NO-releasing properties showed a strong correlation with their ability to induce mitochondrial damage, as evidenced by membrane depolarization. Moreover, the incorporation of specific substituents, such as a furan ring, on the 1,2,4-oxadiazole moiety introduced an additional mechanism of action through the induction of reactive oxygen species. Conclusions: Analysis of cancer cell death confirmed that these compounds acted through a multimodal mechanism dependent on both NO release and the specific substituents on the 1,2,4-oxadiazole moiety.<\/jats:p>","DOI":"10.3390\/pharmaceutics17111494","type":"journal-article","created":{"date-parts":[[2025,11,19]],"date-time":"2025-11-19T11:17:27Z","timestamp":1763551047000},"page":"1494","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Bis-Oxadiazole Assemblies as NO-Releasing Anticancer Agents"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-2297-9781","authenticated-orcid":false,"given":"Egor M.","family":"Matnurov","sequence":"first","affiliation":[{"name":"Drug Discovery Lab, Department of Chemistry, City University of Hong Kong, 83 Tat Chee Avenue, Hong Kong SAR, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6117-829X","authenticated-orcid":false,"given":"Irina A.","family":"Stebletsova","sequence":"additional","affiliation":[{"name":"N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 47 Leninsky Prosp., 119991 Moscow, Russia"},{"name":"Higher Chemical College of the Russian Academy of Sciences, D.I. Mendeleev University of Chemical Technology of Russia, 9 Miusskaya Square, 125047 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7862-2895","authenticated-orcid":false,"given":"Alexander A.","family":"Larin","sequence":"additional","affiliation":[{"name":"N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 47 Leninsky Prosp., 119991 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0012-8536","authenticated-orcid":false,"given":"Jemma","family":"Arakelyan","sequence":"additional","affiliation":[{"name":"Drug Discovery Lab, Department of Chemistry, City University of Hong Kong, 83 Tat Chee Avenue, Hong Kong SAR, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6867-7534","authenticated-orcid":false,"given":"Ivan V.","family":"Ananyev","sequence":"additional","affiliation":[{"name":"N.S. Kurnakov Institute of General and Inorganic Chemistry, Russian Academy of Sciences, GSP-1, Leninsky prospect, 31, 119991 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3214-1433","authenticated-orcid":false,"given":"Artem L.","family":"Gushchin","sequence":"additional","affiliation":[{"name":"A.V. Nikolaev Institute of Inorganic Chemistry, Siberian Branch of Russian Academy of Sciences, 3 Academician Lavrentiev Ave., 630090 Novosibirsk, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0203-1025","authenticated-orcid":false,"given":"Leonid L.","family":"Fershtat","sequence":"additional","affiliation":[{"name":"N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 47 Leninsky Prosp., 119991 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2009-7837","authenticated-orcid":false,"given":"Maria V.","family":"Babak","sequence":"additional","affiliation":[{"name":"Drug Discovery Lab, Department of Chemistry, City University of Hong Kong, 83 Tat Chee Avenue, Hong Kong SAR, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"407","DOI":"10.3892\/ijo.2018.4661","article-title":"From chemotherapy to biological therapy: A review of novel concepts to reduce the side effects of systemic cancer treatment (Review)","volume":"54","author":"Schirrmacher","year":"2019","journal-title":"Int. J. Oncol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1038\/s41586-019-1730-1","article-title":"A view on drug resistance in cancer","volume":"575","author":"Vasan","year":"2019","journal-title":"Nature"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Bukowski, K., Kciuk, M., and Kontek, R. (2020). Mechanisms of Multidrug Resistance in Cancer Chemotherapy. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21093233"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2256","DOI":"10.1021\/acs.jmedchem.8b01303","article-title":"Alkyl Sulfinates: Radical Precursors Enabling Drug Discovery Miniperspective","volume":"62","author":"Smith","year":"2019","journal-title":"J. Med. Chem."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2976","DOI":"10.1021\/acs.accounts.7b00428","article-title":"The Evolution of Chemical High-Throughput Experimentation To Address Challenging Problems in Pharmaceutical Synthesis","volume":"50","author":"Krska","year":"2017","journal-title":"Acc. Chem. Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1126","DOI":"10.1038\/nchem.2587","article-title":"New ligands for nickel catalysis from diverse pharmaceutical heterocycle libraries","volume":"8","author":"Hansen","year":"2016","journal-title":"Nat. Chem."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"799","DOI":"10.1126\/science.aas8961","article-title":"Heterobiaryl synthesis by contractive C\u2013C coupling via P(V) intermediates","volume":"362","author":"Hilton","year":"2018","journal-title":"Science"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"4265","DOI":"10.1021\/acs.jmedchem.8b01610","article-title":"A Survey of the Structures of US FDA Approved Combination Drugs","volume":"62","author":"Das","year":"2019","journal-title":"J. Med. Chem."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"10257","DOI":"10.1021\/jm501100b","article-title":"Analysis of the Structural Diversity, Substitution Patterns, and Frequency of Nitrogen Heterocycles among U.S. FDA Approved Pharmaceuticals","volume":"57","author":"Vitaku","year":"2014","journal-title":"J. Med. Chem."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Kerru, N., Gummidi, L., Maddila, S., and Gangu, K.K. (2020). A Review on Recent Advances in Nitrogen-Containing Molecules and Their Biological Applications. Molecules, 25.","DOI":"10.3390\/molecules25081909"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"941","DOI":"10.1080\/17460441.2017.1344400","article-title":"The latest advances in the discovery of nitric oxide hybrid drug compounds","volume":"12","author":"Serafim","year":"2017","journal-title":"Expert Opin. Drug. Discov."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"414","DOI":"10.1002\/ijch.201800178","article-title":"Natural Product Chemistry for Nitric Oxide Based Therapeutics","volume":"59","author":"Bryan","year":"2019","journal-title":"Isr. J. Chem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"7617","DOI":"10.1021\/acs.jmedchem.6b01672","article-title":"Nitric Oxide Donor-Based Cancer Therapy: Advances and Prospects","volume":"60","author":"Huang","year":"2017","journal-title":"J. Med. Chem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1091","DOI":"10.1021\/cr000040l","article-title":"Nitric Oxide Donors:\u2009 Chemical Activities and Biological Applications","volume":"102","author":"Wang","year":"2002","journal-title":"Chem. Rev."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Fershtat, L.L., and Zhilin, E.S. (2021). Recent Advances in the Synthesis and Biomedical Applications of Heterocyclic NO-Donors. Molecules, 26.","DOI":"10.3390\/molecules26185705"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1152\/japplphysiol.00167.2017","article-title":"Comparison of the vasodilatory effects of sodium nitroprusside vs. nitroglycerin","volume":"123","author":"Ranadive","year":"2017","journal-title":"J. Appl. Physiol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"622","DOI":"10.1002\/cmdc.201700113","article-title":"Molecular Hybridization Tools in the Development of Furoxan-Based NO-Donor Prodrugs","volume":"12","author":"Fershtat","year":"2017","journal-title":"ChemMedChem"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2317","DOI":"10.1016\/j.tetlet.2018.04.070","article-title":"Recent advances in the synthesis and functionalization of 1,2,5-oxadiazole 2-oxides","volume":"59","author":"Makhova","year":"2018","journal-title":"Tetrahedron Lett."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"5346","DOI":"10.1002\/cptc.202000157","article-title":"Novel Arylazo-1,2,5-oxadiazole Photoswitches: Synthesis, Photoisomerization and Nitric Oxide Releasing Properties","volume":"4","author":"Zhilin","year":"2020","journal-title":"ChemPhotoChem"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2644","DOI":"10.1002\/ajoc.202100475","article-title":"Ring Distortion Diversity-Oriented Approach to Fully Substituted Furoxans and Isoxazoles","volume":"10","author":"Chaplygin","year":"2021","journal-title":"Asian J. Org. Chem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"3673","DOI":"10.1055\/a-1529-7678","article-title":"Five-Membered Hetarene N-Oxides: Recent Advances in Synthesis and Reactivity","volume":"53","author":"Fershtat","year":"2021","journal-title":"Synthesis"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Stebletsova, I.A., Larin, A.A., Ananyev, I.V., and Fershtat, L.L. (2023). Regioselective Synthesis of NO-Donor (4-Nitro-1,2,3-triazolyl)furoxans via Eliminative Azide\u2013Olefin Cycloaddition. Molecules, 28.","DOI":"10.3390\/molecules28196969"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1007\/s00706-020-02553-1","article-title":"Synthesis of 1,2,4-oxadiazole derivatives: Anticancer and 3D QSAR studies","volume":"151","author":"Vaidya","year":"2020","journal-title":"Monatsh. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"103754","DOI":"10.1016\/j.bioorg.2020.103754","article-title":"Synthesis and SAR studies of novel 1,2,4-oxadiazole-sulfonamide based compounds as potential anticancer agents for colorectal cancer therapy","volume":"98","author":"Shamsi","year":"2020","journal-title":"Bioorg. Chem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"14284","DOI":"10.1002\/chem.201903526","article-title":"Straightforward Access to the Nitric Oxide Donor Azasydnone Scaffold by Cascade Reactions of Amines","volume":"25","author":"Zhilin","year":"2019","journal-title":"Chem. Eur. J."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1017","DOI":"10.1111\/cbdd.13918","article-title":"Antiaggregant effects of (1,2,5-oxadiazolyl)azasydnone ring assemblies as novel antiplatelet agents","volume":"100","author":"Zhilin","year":"2022","journal-title":"Chem. Biol. Drug Des."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1863","DOI":"10.1055\/a-2011-7264","article-title":"NOBF4-Mediated Assembly of the Sydnone Imine Scaffold in the Synthesis of Double Nitric Oxide Donors","volume":"55","author":"Shuvaev","year":"2023","journal-title":"Synthesis"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"6686","DOI":"10.1039\/D3GC01601C","article-title":"Empowering Strategies of Electrochemical N-N Bond Forming Reactions: Direct Access to Previously Neglected 1,2,3-Triazole 1-Oxides","volume":"25","author":"Titenkova","year":"2023","journal-title":"Green Chem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1016\/j.mencom.2021.01.012","article-title":"Design and synthesis of pyrazolo[3,4-d]pyridazine 5,6-dioxides as novel NO-donors","volume":"31","author":"Kulikov","year":"2021","journal-title":"Mendeleev Commun."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"57","DOI":"10.2174\/1389557053402864","article-title":"Pharmacological properties of furoxans and benzofuroxans: Recent developments","volume":"5","author":"Cerecetto","year":"2005","journal-title":"Mini-Rev. Med. Chem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1016\/S0223-5234(01)01265-X","article-title":"1,2,5-Oxadiazole N-oxide derivatives as potential anti-cancer agents: Synthesis and biological evaluation. Part IV","volume":"36","author":"Boiani","year":"2001","journal-title":"Eur. J. Med. Chem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1651","DOI":"10.1002\/jhet.4675","article-title":"The current scenario of furoxan hybrids with anticancer potential","volume":"60","author":"Shi","year":"2023","journal-title":"J. Heterocycl. Chem."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"5228","DOI":"10.1039\/D3RA00189J","article-title":"Recent progress in synthesis and application of furoxan","volume":"13","author":"Youssef","year":"2023","journal-title":"RSC Adv."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Sinha, B.K., Perera, L., and Cannon, R.E. (2021). NCX-4040, a Unique Nitric Oxide Donor, Induces Reversal of Drug-Resistance in Both ABCB1- and ABCG2-Expressing Multidrug Human Cancer Cells. Cancers, 13.","DOI":"10.3390\/cancers13071680"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"113740","DOI":"10.1016\/j.bcp.2019.113740","article-title":"Small molecules for great solutions: Can nitric oxide-releasing nanomaterials overcome drug resistance in chemotherapy?","volume":"176","author":"Pieretti","year":"2020","journal-title":"Biochem. Pharmacol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"34266","DOI":"10.1039\/C8RA06360E","article-title":"Design, synthesis and biological evaluation of novel nitric oxide-donating podophyllotoxin derivatives as potential antiproliferative agents against multi-drug resistant leukemia cells","volume":"8","author":"Zhang","year":"2018","journal-title":"RSC Adv."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"250","DOI":"10.24820\/ark.5550190.p010.229","article-title":"Synthesis, structural characterization and cytotoxic activity of heterocyclic compounds containing the furoxan ring","volume":"2017","author":"Kulikov","year":"2017","journal-title":"Arkivoc"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1007\/s11172-019-2431-5","article-title":"Hetarylfuroxans: Cytotoxic eff ect and induction of apoptosis in chronic myeloid leukemia K562 cells","volume":"68","author":"Pukhov","year":"2019","journal-title":"Russ. Chem. Bull. Int. Ed."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Stebletsova, I.A., Larin, A.A., Matnurov, E.M., Ananyev, I.V., Babak, M.V., and Fershtat, L.L. (2025). Exploring the anticancer potential of NO-donor oxadiazole assemblies against malignant pleural mesothelioma. Pharmaceutics, 17.","DOI":"10.3390\/pharmaceutics17020230"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1016\/j.mencom.2018.11.010","article-title":"New hybrid furoxan structures with antiaggregant activity","volume":"28","author":"Larin","year":"2018","journal-title":"Mendeleev Commun."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/j.mencom.2018.01.016","article-title":"Antiaggregant activity of water-soluble furoxans","volume":"28","author":"Ustyuzhanina","year":"2018","journal-title":"Mendeleev Commun."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1016\/j.mencom.2016.11.018","article-title":"New insight into the antiaggregant activity of furoxans","volume":"26","author":"Ustyuzhanina","year":"2016","journal-title":"Mendeleev Commun."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1605","DOI":"10.1111\/j.1476-5381.1995.tb14946.x","article-title":"Cardiovascular actions of the furoxan CAS 1609, a novel nitric oxide donor","volume":"114","author":"Bohn","year":"1995","journal-title":"Br. J. Pharmacol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"5635","DOI":"10.1016\/j.ejmech.2010.09.016","article-title":"Convenient synthesis and biological profile of 5-amino-substituted 1,2,4-oxadiazole derivatives","volume":"45","author":"Ispikoudi","year":"2010","journal-title":"Eur. J. Med. Chem."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1016\/j.bioorg.2019.02.043","article-title":"Novel aryl carboximidamides and 3-aryl-1,2,4-oxadiazoles analogues of naproxen as dual selective COX-2\/15-LOX inhibitors: Design, synthesis and Docking studies","volume":"85","author":"Youssif","year":"2019","journal-title":"Bioorg. Chem."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"106350","DOI":"10.1016\/j.rmed.2021.106350","article-title":"The role of nitric oxide in pleural disease","volume":"179","author":"Kotsiou","year":"2021","journal-title":"Respir. Med."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"880","DOI":"10.1054\/bjoc.2000.1384","article-title":"Expression of inducible nitric oxide synthase in healthy pleura and in malignant mesothelioma","volume":"83","author":"Soini","year":"2000","journal-title":"Br. J. Cancer"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1038\/sj.bjc.6604421","article-title":"Cisplatin and vinorelbine first-line chemotherapy in non-resectable malignant pleural mesothelioma","volume":"99","author":"Sorensen","year":"2008","journal-title":"Br. J. Cancer"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1016\/S0005-2728(99)00025-0","article-title":"Nitric oxide and mitochondrial respiration","volume":"1411","author":"Brown","year":"1999","journal-title":"Biochim. Biophys. Acta (BBA) Bioenerg."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1021\/tx3003824","article-title":"Reactive Metabolites in the Biotransformation of Molecules Containing a Furan Ring","volume":"26","author":"Peterson","year":"2013","journal-title":"Chem. Res. Toxicol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1093\/toxres\/tfad025","article-title":"Assessment of the oxidative damage and apoptotic pathway related to furan cytotoxicity in cultured mouse Leydig cells","volume":"12","author":"Aydin","year":"2023","journal-title":"Toxicol. Res."},{"key":"ref_52","unstructured":"Bruker (2018). APEX-III, Bruker AXS Inc."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1107\/S1600576714022985","article-title":"Comparison of silver and molybdenium microfocus X-ray sources for single-crystal structure determination","volume":"48","author":"Krause","year":"2015","journal-title":"J. Appl. Cryst."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1107\/S2053273314026370","article-title":"SHELXT\u2014Integrated space-group and crystal structure determination","volume":"71","author":"Sheldrick","year":"2015","journal-title":"Acta Crystallogr. Sect. A"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1107\/S2053229614024218","article-title":"Crystal structure refinement with SHELXL","volume":"71","author":"Sheldrick","year":"2015","journal-title":"Cryst. Struct. Commun."},{"key":"ref_56","unstructured":"Frisch, M.J., Trucks, G.W., Schlegel, H.B., Scuseria, G.E., Robb, M.A., Cheeseman, J.R., Scalmani, G., Barone, V., Petersson, G.A., and Nakatsuji, H. (2016). Gaussian 09, Revision D.01, Gaussian, Inc."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"9982","DOI":"10.1063\/1.472933","article-title":"Rationale for mixing exact exchange with density functional approximations","volume":"105","author":"Perdew","year":"1996","journal-title":"J. Chem. Phys."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"6158","DOI":"10.1063\/1.478522","article-title":"Toward reliable density functional methods without adjustable parameters: The PBE0 model","volume":"110","author":"Adamo","year":"1999","journal-title":"J. Chem. Phys."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1456","DOI":"10.1002\/jcc.21759","article-title":"Effect of the damping function in dispersion corrected density functional theory","volume":"32","author":"Grimme","year":"2011","journal-title":"J. Comput. Chem."}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/17\/11\/1494\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,21]],"date-time":"2025-11-21T05:24:02Z","timestamp":1763702642000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/17\/11\/1494"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,19]]},"references-count":59,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2025,11]]}},"alternative-id":["pharmaceutics17111494"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics17111494","relation":{},"ISSN":["1999-4923"],"issn-type":[{"type":"electronic","value":"1999-4923"}],"subject":[],"published":{"date-parts":[[2025,11,19]]}}}