{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T20:58:24Z","timestamp":1791665904753,"version":"4.3.4"},"reference-count":122,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T00:00:00Z","timestamp":1784592000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000780","name":"European Union","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100000780","id-type":"DOI","asserted-by":"crossref"}]},{"id":[{"id":"https:\/\/ror.org\/019w4f821","id-type":"ROR","asserted-by":"publisher"}]},{"name":"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":["Molecules"],"abstract":"<jats:p>Valproic acid is a clinically important therapeutic agent whose biological properties have stimulated the development of structurally modified derivatives with improved pharmacological profiles. In the present study, nine amino\u2013valproic acid hybrids were synthesized by a rapid mechanochemical approach using a planetary ball mill under solvent-minimized conditions. The synthesized compounds were formulated in a newly developed deep eutectic solvent composed of urea and propylene glycol (1:4 molar ratio), which was characterized by solvatochromic and Kamlet\u2013Taft analyses. The biological activities of the derivatives were evaluated by hydrogen peroxide scavenging activity (HPSA), hydroxyl radical-scavenging activity (HRSA), and inhibition of albumin denaturation (IAD) assays. Among the investigated compounds, derivative 3h exhibited the highest biological activity, showing IC50 values of 291 \u00b5M and 163 \u00b5M in the HPSA and HRSA assays, respectively, and the strongest anti-inflammatory activity in the IAD assay. All synthesized derivatives demonstrated lower IC50 values than ibuprofen in the albumin denaturation model. Dose\u2013response relationships were analyzed using four- and five-parameter logistic models, with the 5PL model providing a statistically superior fit to the experimental data. Lipophilicity measurements and in silico studies further supported the favorable physicochemical profile of the synthesized compounds. These results identify compound 3h as the most promising derivative and demonstrate the potential of mechanochemical synthesis for the preparation of biologically active valproic acid hybrids.<\/jats:p>","DOI":"10.3390\/molecules31142535","type":"journal-article","created":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T15:17:52Z","timestamp":1784647072000},"page":"2535","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Mechanochemical Synthesis of Valproic Acid-Based Hybrids: Antioxidant, Anti-Inflammatory, and In Silico Evaluation"],"prefix":"10.3390","volume":"31","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\/0000-0002-4662-3735","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"}]},{"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"}]},{"given":"Ovidiu","family":"Cri\u0219an","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\/0000-0002-0314-6553","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"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3655","DOI":"10.1039\/D4SU00385C","article-title":"Comparison of traditional and mechanochemical production processes for nine active pharmaceutical ingredients (APIs)","volume":"2","year":"2024","journal-title":"RSC Sustain."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"16301","DOI":"10.1021\/acssuschemeng.9b03319","article-title":"Investigations of thermally controlled mechanochemical milling reactions","volume":"7","author":"Cindro","year":"2019","journal-title":"ACS Sustain. 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