Mechanochemical Synthesis of Valproic Acid-Based Hybrids: Antioxidant, Anti-Inflammatory, and In Silico Evaluation

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-valproic 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-Taft 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 µM and 163 µM 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-response 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.