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

  • Bioorg Med Chem Lett. 2025 Sep 1:125-126:130266. doi: 10.1016/j.bmcl.2025.130266.
Zhixian Zhang  1 ,  Qianhui Shen  2 ,  Yanping Chen  1 ,  Zhi Liang  1 ,  Yuan Liu  1 ,  Yu Ren  1 ,  Cailv Wei  1 ,  Kang Jia  2 ,  Chao Ding  1 ,  Shisong Wang  1 ,  Rongbiao Pi  3
Affiliations
  • 1. School of Medicine, Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, P.R. China.
  • 2. School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, P.R. China.
  • 3. School of Medicine, Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, P.R. China; International Joint Laboratory (SYSU-PolyU HK) of Novel Anti-Dementia Drugs of Guangdong, Guangzhou, 510006, P.R. China. Electronic address: [email protected].
PMID: 40412448 DOI: 10.1016/j.bmcl.2025.130266
Abstract

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.

Keywords
BDNF; Cinnamanilide; N-oxide; Pharmacokinetics; Solubility.
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