2. Academic Validation
  3. Discovery and structure-activity relationship of cannabidiol aminoquinones as anti-Alzheimer's agents via dual modulation of Nrf2/HO-1 and TLR4/NF-κB pathways

Discovery and structure-activity relationship of cannabidiol aminoquinones as anti-Alzheimer's agents via dual modulation of Nrf2/HO-1 and TLR4/NF-κB pathways

  • Bioorg Chem. 2026 May:172:109590. doi: 10.1016/j.bioorg.2026.109590.
Ziwen Zhang 1,  Shan Gao 2,  Jie Zhao 2,  Xiaodan Liu 2,  Fangfang Zuo 2,  Yinxin Wu 2,  Ling Ai 3,  Wenjian Tang 4
Affiliations

Affiliations

  • 1 Jiaxing Maternity and Child Health Care Hospital, Affiliated Women and Children Hospital, Jiaxing University, Zhejiang 314000, China.
  • 2 School of Pharmacy, Anhui Medical University, Hefei 230032, China.
  • 3 Jiaxing Maternity and Child Health Care Hospital, Affiliated Women and Children Hospital, Jiaxing University, Zhejiang 314000, China. Electronic address: [email protected].
  • 4 School of Pharmacy, Anhui Medical University, Hefei 230032, China. Electronic address: [email protected].
PMID: 41643512 DOI: 10.1016/j.bioorg.2026.109590
Abstract

Neuroinflammation and oxidative stress are recognized as key drivers of neuronal death and the progression of neurodegenerative diseases. At the same time, they serve as central hubs linking the major pathological hallmarks of Alzheimer's disease (AD), including Aβ aggregation, Tau Protein hyperphosphorylation, neurofibrillary tangle formation, and neuronal injury. In this study, we screened natural active molecules of cannabidiol (CBD) and its derivatives, and conducted molecular docking simulations. A class of CBD aminoquinone scaffolds with potential anti-AD activity was identified, and 32 CBD aminoquinone derivatives were synthesized for comprehensive in vitro and in vivo evaluation. Among them, compound G-12 with p-F-aniline moiety exhibited potent anti-inflammatory activity (IC50 = 1.39 μM), outstanding neuroprotective effects (IC50 = 1.29 μM), and prominent behavioral manifestations. In addition, G-12 displayed acceptable in vivo pharmacokinetic (PK) properties. The superior performance of G-12 indicated that through the Nrf2/HO-1 oxidative stress pathway, it affected the TLR4/NF-κB inflammatory pathway, inhibited neuroinflammation, and thereby influenced Aβ aggregation, protecting neurons. This strategy that links several major pathological features of AD is effective in combating AD. G-12 is also a lead compound with the potential to be developed into a multifunctional drug for AD.

Keywords

Alzheimer's disease; Aminoquinone; Cannabidiol (CBD); Neuroinflammation; Nrf2/HO-1 pathway; Structure-activity relationship (SAR).

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