Design to neuroprotection: a blood brain barrier permeable selective HDAC3 inhibitor active against chemical and viral insults.

Neuronal loss in neurodegenerative diseases is mediated by oxidative stress, neuroinflammation, and epigenetic dysregulation, with histone deacetylase 3 (HDAC3) playing a central role in inflammatory signaling and neuronal damage. We synthesized 12 compounds and identified the lead compound 9c as a potent and selective HDAC3 inhibitor, with an IC50 of 0.75 μM and at least 27-fold selectivity over other HDAC isoforms. Compound 9c exhibited significant neuroprotection against hydrogen peroxide (H2O2) induced oxidative stress in N2A cells and Japanese encephalitis virus (JEV)-induced cell death in SH-SY5Y cells. Further western blot analysis revealed upregulation of neuronal markers (CREB, BDNF, and synaptophysin) and increased histone acetylation (Ac-H3K9, Ac-H3K27, and Ac-H4K8). Treatment of SH-SY5Y cells with 9c during JEV infection reduces virus-induced caspase-3/7 activity. In addition, quantitative real-time PCR analysis revealed that 9c reduces the expression of pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6) during JEV infection. Neurite outgrowth and neuronal differentiation assays demonstrated that 9c promotes neuronal growth and maturation. Pharmacokinetic studies showed substantial brain penetration of 9c, with a C max of 1.84 μg mL-1 at 1 h and t 1/2 of 4 h. Collectively, these findings suggest that selective HDAC3 inhibition by 9c confers neuroprotection, supporting its potential as a promising therapeutic candidate for neurodegenerative disorders.