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  3. Scutellarein derivatives with histamine H3 receptor antagonism and cholinesterase inhibitory potency as multi target-directed ligands for possible Alzheimer's disease therapy

Scutellarein derivatives with histamine H3 receptor antagonism and cholinesterase inhibitory potency as multi target-directed ligands for possible Alzheimer's disease therapy

  • Bioorg Chem. 2024 Oct:151:107704. doi: 10.1016/j.bioorg.2024.107704.
Jiao Chen 1,  Zhu He 1,  Keke Luo 2,  Qianhen Luo 3,  Yujie Wang 4,  Ting Liu 3,  Li Li 2,  Zeqin Dai 2,  Shenggang Yang 5,  Yongjun Li 1,  Yonglong Zhao 2,  Lei Tang 6,  Xiaozhong Fu 7
Affiliations

Affiliations

  • 1 School of Pharmacy, Guizhou Medical University, Guiyang 550004, China; Guizhou Provincial Key Laboratory of Pharmaceutics, Guizhou Medical University, Guiyang 550004, China; National Engineering Research Center of Miao's Medicines & Engineering Research Center for the Development and Application of Ethnic Medicine and TCM, Ministry of Education, Guiyang 550004, Guizhou, China.
  • 2 School of Pharmacy, Guizhou Medical University, Guiyang 550004, China; Guizhou Provincial Key Laboratory of Pharmaceutics, Guizhou Medical University, Guiyang 550004, China.
  • 3 Guizhou Provincial Key Laboratory of Pharmaceutics, Guizhou Medical University, Guiyang 550004, China; National Engineering Research Center of Miao's Medicines & Engineering Research Center for the Development and Application of Ethnic Medicine and TCM, Ministry of Education, Guiyang 550004, Guizhou, China.
  • 4 State Key Laboratory of Functions and Applications of Medicinal Plants & College of Pharmacy, Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D, Guizhou Medical University, Guiyang 550025, China.
  • 5 School of Pharmacy, Guizhou Medical University, Guiyang 550004, China; State Key Laboratory of Functions and Applications of Medicinal Plants & College of Pharmacy, Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D, Guizhou Medical University, Guiyang 550025, China.
  • 6 State Key Laboratory of Functions and Applications of Medicinal Plants & College of Pharmacy, Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D, Guizhou Medical University, Guiyang 550025, China. Electronic address: tlei1974@163.com.
  • 7 School of Pharmacy, Guizhou Medical University, Guiyang 550004, China; Guizhou Provincial Key Laboratory of Pharmaceutics, Guizhou Medical University, Guiyang 550004, China; National Engineering Research Center of Miao's Medicines & Engineering Research Center for the Development and Application of Ethnic Medicine and TCM, Ministry of Education, Guiyang 550004, Guizhou, China. Electronic address: xiaozhong_fu@sina.com.
PMID: 39126870 DOI: 10.1016/j.bioorg.2024.107704
Abstract

A series of scutellarein 7-l-amino acid carbamate-4'-cycloalkylamine propyl ether conjugates were designed and synthesized for the first time as multifunctional agents for Alzheimer's disease (AD) therapy. The designed compounds exhibited more balanced and effective multi-target potency. Among them, compound 11l, l-Valine carbamate derivative of scutellarein cycloheptylamine ether, exhibited the most potent inhibition of electric eel AChE Enzymes and human AChE Enzymes, with an IC50 values of 7.04 μM and 9.73 μM, respectively. Moreover, 11l exhibited more potent H3R antagonistic activities than clobenpropit, with an IC50 value of 1.09 nM. Compound 11l not only displayed excellent inhibition of self- and Cu2+-induced Aβ1-42 aggregation (95.48 % and 88.63 % inhibition, respectively) but also induced the disassembly of self- and Cu2+-induced Aβ fibrils (80.16 % and 89.30 % disaggregation, respectively). Moreover, 11l significantly reduced Tau Protein hyperphosphorylation induced by Aβ25-35. It exhibited effective antioxidant activity and neuroprotective potency, and inhibited RSL3-induced PC12 cell Ferroptosis. Assays of hCMEC/D3 and hPepT1-MDCK cell line permeability indicated that 11l would have optimal blood-brain barrier permeability and intestinal absorption characteristics. In addition, in vivo studies revealed that compound 11l significantly attenuated learning and memory impairment in an AD mouse model. Finally, a pharmacokinetic characterization of 11l indicated favorable druggability and pharmacokinetic properties. Taken together, our results suggest that 11l is a potential candidate for AD treatment and merits further investigation.

Keywords

Acetylcholinesterase; Alzheimer’s disease; Histamine H(3) receptor; Neuroinflammation; Scutellarein.

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