Mechanosynthesis and Biological Evaluation of Valproic Acid–Based Dual-Pharmacophore Hybrids

This study reports the green mechanosynthesis of nine novel hybrid molecules combining valproic acid-a clinically established anticonvulsant, mood stabilizer, and epigenetic modulator-with bioactive 2-phenylethylamine and tryptamine derivatives, which are recognized for their neuromodulatory, antioxidant, and anti-inflammatory properties. The hybrids were efficiently prepared by initially converting valproic acid to its corresponding acid chloride, followed by rapid, solvent-minimized amidation with various substituted amines under optimized planetary ball-milling conditions (500 rpm, 1 minute). This eco-friendly protocol achieved excellent yields (>90%) while drastically reducing chemical waste and energy consumption.

All newly synthesized amide-linked compounds were rigorously characterized using ¹H and ¹³C nuclear magnetic resonance (NMR) spectroscopy, infrared (IR) spectroscopy, and high-resolution mass spectrometry (HRMS). The strategic incorporation of a stable amide bond merges the neuroprotective potential of valproic acid with the radical-scavenging capabilities of the amine scaffolds. Subsequent in vitro evaluations, facilitated by a novel biodegradable deep eutectic solvent (urea and propylene glycol), demonstrated that these dual-pharmacophore hybrids exhibit potent hydrogen peroxide and hydroxyl radical-scavenging activities, alongside superior anti-inflammatory effects in albumin denaturation assays compared to standard references. Supported by favorable in silico molecular docking to human serum albumin, this work highlights how sustainable, solvent-minimized mechanochemistry can effectively accelerate the development of multifunctional, structurally optimized drug leads for neurological and inflammatory therapeutic research.