Design and characterization of N-oxide cinnamanilide derivative PX5-9: Improved solubility and BDNF upregulation.

Compound 5, a cinnamanilide derivative, upregulates brain derivated neurotrophic factor (BDNF) expression but with low soluablity. In this study, PX5-9, a N-oxide derivative of 5, demonstrated significant protective effects in the HT22 glutamate-induced toxicity model and showed no significant toxicity at 30 μM. Western blot analysis confirmed that PX5-9 increased BDNF levels similar to 5. Solubility tests revealed a significant improvement in PX5-9 (37.10 ± 0.33 μg/mL) compared to 5 (< 15 ng/mL). Pharmacokinetic studies of PX5-9 revealed favorable properties, fast absorption and also can be transformated into parent compound 5, suggesting it is a potential candidate for these diseases involving with BDNF. The N-oxide modification might be a good prodrug design to enhance solubility while preserving biological activity.