Ferrocenyl substitution turns valproate into a glutamate decarboxylase inhibitor.

2-(Ferrocenylmethyl)pentanoic acid (Fc-VPA), a ferrocenyl analog of valproic acid (VPA), was synthesized, fully characterized and its effect on glutamate decarboxylase (GAD) evaluated in mouse brain homogenates using an HPLC assay. Fc-VPA produced robust, concentration-dependent GAD inhibition (IC50 = 51 ± 4 μM), comparable to 3-mercaptopropanoic acid (3-MPA; IC50 = 38 ± 2 μM), whereas VPA showed weak/biphasic effects under identical conditions. Blind docking to human GAD (PDB 2OKK) supported the trend: Fc-VPA achieved a modestly higher XSCORE than VPA (5.287 vs 4.887) and engaged a broader interaction network within the active site. These findings show that ferrocenyl substitution markedly reprograms VPA's enzyme interaction profile from weak modulation to potent inhibition. The pharmacological desirability of GAD inhibition by Fc-VPA remains to be established in cellular and in vivo models.