{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T19:53:52Z","timestamp":1790279632429,"version":"4.1.0"},"reference-count":51,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2024,1,19]],"date-time":"2024-01-19T00:00:00Z","timestamp":1705622400000},"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>Several organometallic complexes based on more than twenty different metals have already been approved for medical applications. The aim of the presented research was to obtain complexes of silver and copper with the non-steroidal anti-inflammatory drugs ibuprofen and xanthine alkaloid caffeine and evaluate selected aspects of their bioactivity and biosafety in terms of their future possible applications. The obtained complexes were characterized by Fourier-transform infrared spectroscopy, thermogravimetry, UV-VIS spectroscopy, conductometry, elemental analysis, and bioassays. Cytotoxicity for normal human cells of the CCD-Co18 cell line was evaluated by determining the IC50 value, with metabolic and morphology assessments. It was observed that complexes containing ibuprofen and caffeine exhibited lower toxicity than those with ibuprofen only. Complexes with copper showed lower toxicity towards healthy human fibroblasts compared to silver-based compounds, with an IC50 above 140 \u03bcg mL\u22121. However, in the silver complexes, the presence of caffeine increased the potency of COX-2 inhibition. Antimicrobial effects against different Gram-positive and Gram-negative bacterial strains were evaluated by MIC determination with values less than 20 \u03bcg mL\u22121.<\/jats:p>","DOI":"10.3390\/molecules29020506","type":"journal-article","created":{"date-parts":[[2024,1,19]],"date-time":"2024-01-19T09:46:39Z","timestamp":1705657599000},"page":"506","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Silver and Copper Complexes with Ibuprofen and Caffeine\u2014Preparation and Evaluation of Their Selected Biological Effects"],"prefix":"10.3390","volume":"29","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8307-6577","authenticated-orcid":false,"given":"Anna","family":"Bor\u00f3wka","sequence":"first","affiliation":[{"name":"Department of Animal Physiology and Toxicology, The John Paul II Catholic University of Lublin, Konstantyn\u00f3w Str. 1i, 20-708 Lublin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3125-7402","authenticated-orcid":false,"given":"Anna","family":"Sieros\u0142awska","sequence":"additional","affiliation":[{"name":"Department of Animal Physiology and Toxicology, The John Paul II Catholic University of Lublin, Konstantyn\u00f3w Str. 1i, 20-708 Lublin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6306-224X","authenticated-orcid":false,"given":"Andrea","family":"Baier","sequence":"additional","affiliation":[{"name":"Department of Animal Physiology and Toxicology, The John Paul II Catholic University of Lublin, Konstantyn\u00f3w Str. 1i, 20-708 Lublin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4322-5045","authenticated-orcid":false,"given":"Anna","family":"Rymuszka","sequence":"additional","affiliation":[{"name":"Department of Animal Physiology and Toxicology, The John Paul II Catholic University of Lublin, Konstantyn\u00f3w Str. 1i, 20-708 Lublin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1108-111X","authenticated-orcid":false,"given":"El\u017cbieta","family":"Olszewska","sequence":"additional","affiliation":[{"name":"Department of General and Coordination Chemistry and Crystallography, Faculty of Chemistry, Maria Curie-Sklodowska University in Lublin, Maria Curie-Sklodowska Sq. 3, 20-031 Lublin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,1,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"7570","DOI":"10.1039\/D0RA00100G","article-title":"Enhancement of ibuprofen solubility and skin permeation by conjugation with l-valine alkyl esters","volume":"10","author":"Janus","year":"2020","journal-title":"RSC Adv."},{"key":"ref_2","first-page":"223","article-title":"Study of physical interaction between ibuprofen and caffeine and its influence on solubility and hygroscopicity of ibuprofen","volume":"7","author":"Nugrahani","year":"2015","journal-title":"Int. J. Pharm. Sci."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Belayneh, A., and Molla, F. (2020). The Effect of Coffee on Pharmacokinetic Properties of Drugs: A Review. BioMed Res. Int., 2020.","DOI":"10.1155\/2020\/7909703"},{"key":"ref_4","unstructured":"(2023, July 22). Caffeine\u2014StatPearls\u2014NCBI Bookshelf, Available online: https:\/\/www.ncbi.nlm.nih.gov\/books\/NBK519490\/."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1016\/0009-2797(73)90046-X","article-title":"Inhibition of repair of UV-damaged DNA by caffeine and mutation induction in Chinese hamster cells","volume":"5","author":"Trosko","year":"1973","journal-title":"Chem. Biol. Interact."},{"key":"ref_6","first-page":"465","article-title":"Caffeine activates tumor suppressor PTEN in sarcoma cells","volume":"39","author":"Miwa","year":"2011","journal-title":"Int. J. Oncol."},{"key":"ref_7","first-page":"543","article-title":"Caffeine inhibits the proliferation of liver cancer cells and activates the MEK\/ERK\/EGFR signaling pathway Basic Clin","volume":"102","author":"Okano","year":"2008","journal-title":"Pharmacol. Toxicol."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Al-Ansari, M.M., and Aboussekhra, A. (2014). Caffeine mediates sustained inactivation of breast cancer-associated myofibroblasts via up-regulation of tumor suppressor genes. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0090907"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2205","DOI":"10.1016\/S0028-3908(00)00045-9","article-title":"Effects of caffeine and paracetamol alone or in combination with acetylsalicylic acid on prostaglandin E(2) synthesis in rat microglial cells","volume":"39","author":"Fiebich","year":"2000","journal-title":"Neuropharmacology"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Bindu, S., Mazumder, S., and Bandyopadhyay, U. (2020). Non-steroidal anti-inflammatory drugs (NSAIDs) and organ damage: A current perspective. Biochem. Pharmacol., 180.","DOI":"10.1016\/j.bcp.2020.114147"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1186\/s13578-016-0076-8","article-title":"A novel class of copper(II)- and zinc(II)-bound non-steroidal anti-inflammatory drugs that inhibits acute inflammation in vivo","volume":"6","author":"Puranik","year":"2016","journal-title":"Cell Biosci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"727","DOI":"10.1021\/acs.chemrev.8b00685","article-title":"Introduction: Metals in medicine","volume":"119","author":"Franz","year":"2019","journal-title":"Chem. Rev."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"3048","DOI":"10.1002\/ejic.201501480","article-title":"Non-steroidal anti-inflammatory drugs (NSAIDs) in metal complexes and their effect at the cellular level","volume":"2016","author":"Banti","year":"2016","journal-title":"Eur. J. Inorg. Chem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2436","DOI":"10.1080\/00958972.2017.1337897","article-title":"New complexes of Zn(II) with the anti-inflammatory non-steroidal drug, ibuprofen and nitrogen donor ligands. Synthesis, characterization and biological activity","volume":"70","author":"Omar","year":"2017","journal-title":"J. Coord. Chem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"119897","DOI":"10.1016\/j.molliq.2022.119897","article-title":"Synthesis of Cu(II)-caffeine complex as potential therapeutic agent: Studies on antioxidant, anticancer and pharmacological activities","volume":"364","author":"Kisku","year":"2022","journal-title":"J. Mol. Liq."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"876","DOI":"10.1016\/j.ccr.2009.12.018","article-title":"Copper-related diseases: From chemistry to molecular pathology","volume":"254","author":"Crisponi","year":"2010","journal-title":"Coord. Chem. Rev."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1016\/j.ccr.2014.08.002","article-title":"Silver coordination compounds: A new horizon in medicine","volume":"284","author":"Medici","year":"2015","journal-title":"Coord. Chem. Rev."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1002\/bip.20057","article-title":"Spectroscopic behaviour of copper complexes of nonsteroidal anti-inflammatory drugs","volume":"74","author":"Trinchero","year":"2004","journal-title":"Biopolymers"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1080\/15257770.2016.1223305","article-title":"Multispectroscopic studies on the interaction of a copper(II) complex of ibuprofen drug with calf thymus DN","volume":"36","author":"Shahabadi","year":"2017","journal-title":"Nucleosides Nucleotides Nucleic Acids."},{"key":"ref_20","first-page":"320","article-title":"Binuclear copper complexes with non-steroidal anti-inflammatory drugs as studied by electrospray ionization mass spectroscopy","volume":"10","author":"Kowcun","year":"2012","journal-title":"Cent. Eur. J. Chem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/j.molliq.2013.03.005","article-title":"Metal ion interactions with drugs: Electrochemical study of complexation of various bivalent metal ions with nimesulide and ibuprofen","volume":"182","author":"Kaur","year":"2013","journal-title":"J. Mol. Liq."},{"key":"ref_22","first-page":"569","article-title":"Novel Cu(II) complex with non-steroidal anti-inflammatory drugs","volume":"64","author":"Tita","year":"2013","journal-title":"Rev. Chim."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Abbas, A.M., Aboelmagd, A., Kishk, S.M., Nasrallah, H.H., Boyd, W.C., Kalil, H., and Orabi, A.S. (2022). A novel ibuprofen derivative and its complexes: Physicochemical characterization, DFT modeling, docking, in vitro anti-inflammatory studies, and DNA interactions. Molecules, 27.","DOI":"10.3390\/molecules27217540"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Malis, G., Geromichalou, E., Geromichalou, G.D., Hatzidimitriou, A.G., and Psomas, G. (2021). Copper(II) complexes with non-steroidal anti-inflammatory drugs: Structural characterization, in vitro and in silico biological profile. J. Inorg. Biochem., 224.","DOI":"10.1016\/j.jinorgbio.2021.111563"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1149\/1.2928902","article-title":"Treatment of various surfaces with silver and its compounds for topical wound dressings, catheter and other biomedical applications","volume":"11","year":"2008","journal-title":"ECS Trans."},{"key":"ref_26","first-page":"100735","article-title":"Sulfonamide-functionalized silver nanoparticles as an analytical nanoprobe for selective Ni(II) sensing with synergistic antimicrobial activity","volume":"18","author":"Amin","year":"2022","journal-title":"Environ. Nanotechnol. Monit. Manag."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.molstruc.2013.06.034","article-title":"A silver complex with ibuprofen: Synthesis, solid state characterization, DFT calculations and antibacterial assays","volume":"1049","author":"Lancellotti","year":"2013","journal-title":"J. Mol. Struct."},{"key":"ref_28","first-page":"51","article-title":"Novel silver complexes with popular non-steroidal anti-inflammatory drugs","volume":"21","author":"Kafarska","year":"2016","journal-title":"Acta Innov."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"773","DOI":"10.3923\/ijp.2015.773.785","article-title":"Structural, conductometric and antimicrobial investigations of ibuprofen analgesic drug complex with certain metal ions","volume":"11","author":"Naglah","year":"2015","journal-title":"Int. J. Pharm."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/j.inoche.2014.03.039","article-title":"Synthesis, spectroscopic studies and in vitro antibacterial activity of ibuprofen and its derived metal complexes","volume":"45","author":"Nunez","year":"2014","journal-title":"Inorg. Chem. Commun."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"738","DOI":"10.1016\/j.inoche.2011.02.024","article-title":"Chemical, spectroscopic characterization and antibacterial activities of a novel gold(I)-ibuprofen complex","volume":"14","author":"Fiori","year":"2011","journal-title":"Inorg. Chem. Commun."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Nakamoto, K. (2009). Infrared and Raman Spectra of Inorganic and Coordination Compounds: Part B: Applications in Coordination, Organometallic, and Bioinorganic Chemistry, John Wiley and Sons. [6th ed.].","DOI":"10.1002\/9780470405888"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"260","DOI":"10.1080\/19336918.2019.1638691","article-title":"Caffeine inhibits hypoxia-induced renal fibroblast activation by antioxidant mechanism","volume":"13","author":"Nilnumkhum","year":"2019","journal-title":"Cell Adh. Migr."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1111\/joim.13505","article-title":"Lessons from 20 years with COX-2 inhibitors: Importance of dose-response considerations and fair play in comparative trials","volume":"292","author":"Stiller","year":"2022","journal-title":"J. Intern. Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"11693","DOI":"10.1073\/pnas.90.24.11693","article-title":"Selectivity of nonsteroidal antiinflammatory drugs as inhibitors of constitutive and inducible cyclooxygenase","volume":"90","author":"Mitchell","year":"1993","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"564","DOI":"10.1016\/j.foodchem.2011.09.024","article-title":"Bioactivities of crude caffeine: Antioxidant activity, cyclooxygenase-2 inhibition, and enhanced glucose uptake","volume":"131","author":"Chu","year":"2012","journal-title":"Food Chem."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"012004","DOI":"10.1088\/1742-6596\/1146\/1\/012004","article-title":"Interaction of acetaminophen and caffeine towards cyclooxygenase-2 (COX-2) in inhibition of prostaglandin (PGH2) synthesis","volume":"1146","author":"Krisnamurti","year":"2019","journal-title":"J. Phys. Conf. Ser."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1038\/nrd3955","article-title":"Adenosine receptors as drug targets\u2014What are the challenges?","volume":"12","author":"Chen","year":"2013","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1016\/j.trechm.2021.03.006","article-title":"Metal Complexes for Therapeutic Applications","volume":"3","author":"Karges","year":"2021","journal-title":"Trends Chem."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Bhalani, D.V., Nutan, B., Kumar, A., and Singh Chandel, A.K. (2022). Bioavailability enhancement techniques for poorly aqueous soluble drugs and therapeutics. Biomedicines, 10.","DOI":"10.3390\/biomedicines10092055"},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Sharmin, E., and Zafar, F. (2017). Spectroscopic Analyses\u2014Developments and Applications, In Tech.","DOI":"10.5772\/65617"},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Ameh, T., Gibb, M., Stevens, D., Pradhan, S.H., Braswell, E., and Sayes, C.M. (2022). Silver and copper nanoparticles induce oxidative stress in bacteria and mammalian cells. Nanomaterials, 12.","DOI":"10.3390\/nano12142402"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"6","DOI":"10.5530\/gjpb.2022.1.3","article-title":"Silver complexes as anticancer agents: A perspective review","volume":"1","author":"Raju","year":"2022","journal-title":"Ger. J. Pharm. Biomater."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Kalinowska-Lis, U., Felczak, A., Ch\u0119ci\u0144ska, L., Szab\u0142owska-Gadomska, I., Patyna, E., Ma\u0142ecki, M., Lisowska, K., and Ochocki, J. (2016). Antibacterial activity and cytotoxicity of silver(I) complexes of pyridine and (benz)imidazole derivatives. X-ray crystal structure of [Ag(2,6-di(CH2OH)py)2]NO3. Molecules, 21.","DOI":"10.3390\/molecules21020087"},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Radko, L., Stypu\u0142a-Tr\u0119bas, S., Posyniak, A., \u017byro, D., and Ochocki, J. (2019). Silver(I) complexes of the pharmaceutical agents metronidazole and 4-hydroxymethylpyridine: Comparison of cytotoxic profile for potential clinical application. Molecules, 24.","DOI":"10.3390\/molecules24101949"},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Pellei, M., Santini, C., Bagnarelli, L., Caviglia, M., Sgarbossa, P., De Franco, M., Zancato, M., Marzano, C., and Gandin, V. (2023). Novel silver complexes based on phosphanes and ester derivatives of bis(pyrazol-1-yl)acetate ligands targeting TrxR: New promising chemotherapeutic tools relevant to SCLC management. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24044091"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1134\/S0006350922040108","article-title":"Cytotoxicity of silver compounds","volume":"67","author":"Korman","year":"2022","journal-title":"Biophysics"},{"key":"ref_48","unstructured":"(2009). Biological Evaluation of Medical Devices. Tests for in Vitro Cytotoxicity (ISO 10993-5:2009) (Standard No. ISO 10993-5:2009)."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"\u015aliwa, E.I., \u015aliwi\u0144ska-Hill, U., Ba\u017can\u00f3w, B., Siczek, M., K\u0142ak, J., and Smole\u0144ski, P. (2020). Synthesis, structural, and cytotoxic properties of new water-soluble copper(II) complexes based on 2,9-dimethyl-1,10-phenanthroline and their one derivative containing 1,3,5-triaza-7-phosphaadamantane-7-oxide. Molecules, 25.","DOI":"10.3390\/molecules25030741"},{"key":"ref_50","first-page":"415","article-title":"Influence of ascorbic acid on cytotoxic activity of copper an iron ions in vitro","volume":"57","author":"Marczewska","year":"2000","journal-title":"Acta Pol. Pharm."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"5237","DOI":"10.1038\/s41598-019-41063-x","article-title":"Copper(II) complexes as potential anticancer and nonsteroidal anti-inflammatory agents: In vitro and in vivo studies","volume":"9","author":"Hussain","year":"2019","journal-title":"Sci. Rep."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/29\/2\/506\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T13:46:06Z","timestamp":1760103966000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/29\/2\/506"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,1,19]]},"references-count":51,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2024,1]]}},"alternative-id":["molecules29020506"],"URL":"https:\/\/doi.org\/10.3390\/molecules29020506","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,1,19]]}}}