Kumar_2026_Future.Med.Chem__1

AIMS: This study involves the semi-synthetic modification of (+)-usnic acid and the evaluation of the synthesized compounds for neuroprotective effects in scopolamine-injured C6 glial cells. MATERIALS AND METHODS: Usnic acid derivatives were synthesized and characterized using (1)H and (13)C nuclear magnetic resonance (NMR) and high-resolution mass spectrometry (HRMS). Furthermore, compounds were evaluated for their neuroprotective effects using several biochemical assays, including acetylcholinesterase, lipid peroxidation, nitric oxide (NO), reduced glutathione (GSH), oxidized glutathione (GSSG), and GSH/GSSG, reactive oxygen species (ROS), NFkB-p65, proinflammatory cytokines, and mitochondrial membrane potential (MMP). In silico studies were conducted to predict drug-likeness and binding sites for these molecules. RESULTS: (+)-Usnic acid, compounds 6, 13, and 16 showed antioxidative effects by decreasing ROS, malondialdehyde, and NO production in scopolamine-injured C6 glial cells. Additionally, these compounds enhanced the antioxidant effects by restoring the GSH/GSSG ratio and improving mitochondrial function by restoring the MMP in scopolamine-injured C6 glial cells. Moreover, these compounds exhibited anti-inflammatory effects by reducing IL-6 and tumor necrosis factor alpha (TNF-alpha) secretion and NFkB activity in C6 glial cells. In silico studies confirmed that these compounds decreased NO production by binding to neuronal nitric oxide synthase. CONCLUSION: Usnic acid and its derivatives, 6, 13, and 16, increased the survival of scopolamine-injured C6 glial cells.