{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T20:58:25Z","timestamp":1791665905034,"version":"4.3.4"},"reference-count":70,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2025,8,23]],"date-time":"2025-08-23T00:00:00Z","timestamp":1755907200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"European Union\u2019s Next Generation EU program through the National Recovery and Resilience Plan of the Republic of Bulgaria","award":["DUECOS BG-RRP-2.004-0001-C01"],"award-info":[{"award-number":["DUECOS BG-RRP-2.004-0001-C01"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background: Trimetazidine is a clinically established cardioprotective agent with anti-ischemic and antioxidant properties, widely used in the management of coronary artery disease. Combining its metabolic and cytoprotective effects with the potent anti-inflammatory activity of profens presents a promising therapeutic strategy. Methods: Five novel trimetazidine\u2013profen hybrid compounds were synthesized using N,N\u2032-dicyclohexylcarbodiimide-mediated coupling and structurally characterized by NMR and high-resolution mass spectrometry. Their antioxidant activity was evaluated by hydroxyl radical scavenging assays (HRSA), and the anti-inflammatory potential was assessed via the inhibition of albumin denaturation (IAD). Lipophilicity was determined chromatographically. Molecular docking and 100 ns molecular dynamics simulations were performed to investigate the binding modes and stability in human serum albumin (HSA) binding sites. The acute toxicity of the hybrid molecules was predicted in silico using GUSAR software. Results: All synthesized hybrids demonstrated varying degrees of biological activity, with compound 3c exhibiting the most potent antioxidant (HRSA IC\u2085\u2080 = 71.13 \u00b5g\/mL) and anti-inflammatory (IAD IC\u2085\u2080 = 108.58 \u00b5g\/mL) effects. Lipophilicity assays indicated moderate membrane permeability, with compounds 3c and 3d showing favorable profiles. Docking studies revealed stronger binding affinities of S-enantiomers, particularly 3c and 3d, to Sudlow sites II and III in HSA. Molecular dynamics simulations confirmed stable ligand\u2013protein complexes, highlighting compound 3c as maintaining consistent and robust interactions. The toxicity results indicate that most hybrids, particularly compounds 3b\u20133d, exhibit a favorable safety profile compared to the parent trimetazidine. Conclusion: The hybrid trimetazidine\u2013profen compounds synthesized herein, especially compound 3c, demonstrate promising dual antioxidant and anti-inflammatory therapeutic potential. Their stable interaction with serum albumin and balanced physicochemical properties support further development as novel agents for managing ischemic heart disease and associated inflammatory conditions.<\/jats:p>","DOI":"10.3390\/ph18091251","type":"journal-article","created":{"date-parts":[[2025,8,25]],"date-time":"2025-08-25T00:09:32Z","timestamp":1756080572000},"page":"1251","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Trimetazidine\u2013Profen Hybrid Molecules: Synthesis, Chemical Characterization, and Biological Evaluation of Their Racemates"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-2623-0043","authenticated-orcid":false,"given":"Diyana","family":"Dimitrova","sequence":"first","affiliation":[{"name":"Department of Organic Chemistry, Faculty of Chemistry, University of Plovdiv, 24 \u201cTsar Assen\u201d Str., 4000 Plovdiv, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0314-6553","authenticated-orcid":false,"given":"Stanimir","family":"Manolov","sequence":"additional","affiliation":[{"name":"Department of Organic Chemistry, Faculty of Chemistry, University of Plovdiv, 24 \u201cTsar Assen\u201d Str., 4000 Plovdiv, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4662-3735","authenticated-orcid":false,"given":"Iliyan","family":"Ivanov","sequence":"additional","affiliation":[{"name":"Department of Organic Chemistry, Faculty of Chemistry, University of Plovdiv, 24 \u201cTsar Assen\u201d Str., 4000 Plovdiv, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6569-8348","authenticated-orcid":false,"given":"Dimitar","family":"Bojilov","sequence":"additional","affiliation":[{"name":"Department of Organic Chemistry, Faculty of Chemistry, University of Plovdiv, 24 \u201cTsar Assen\u201d Str., 4000 Plovdiv, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nikol","family":"Dimova","sequence":"additional","affiliation":[{"name":"Department of Organic Chemistry, Faculty of Chemistry, University of Plovdiv, 24 \u201cTsar Assen\u201d Str., 4000 Plovdiv, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9397-0388","authenticated-orcid":false,"given":"Gabriel","family":"Marc","sequence":"additional","affiliation":[{"name":"Department of Organic Chemistry, Faculty of Pharmacy, \u201cIuliu Ha\u021bieganu\u201d University of Medicine and Pharmacy, 41 Victor Babe\u0219 Street, RO-400010 Cluj-Napoca, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0297-7697","authenticated-orcid":false,"given":"Smaranda","family":"Oniga","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, Faculty of Pharmacy, \u201cIuliu Ha\u021bieganu\u201d University of Medicine and Pharmacy, 41 Victor Babe\u0219 Street, RO-400010 Cluj-Napoca, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ovidiu","family":"Oniga","sequence":"additional","affiliation":[{"name":"Department of Therapeutic Chemistry, \u201cIuliu Ha\u021bieganu\u201d University of Medicine and Pharmacy, 12 Ion Creang\u0103 Street, RO-400010 Cluj-Napoca, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1159\/000375289","article-title":"The effectiveness of preoperative trimetazidine on myocardial preservation in coronary artery bypass graft patients: A systematic review and meta-analysis","volume":"131","author":"Zhang","year":"2015","journal-title":"Cardiology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"3231","DOI":"10.1038\/s41380-023-02134-8","article-title":"Metabolic regulation to treat bipolar depression: Mechanisms and targeting by trimetazidine","volume":"28","author":"Khanra","year":"2023","journal-title":"Mol. 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