Design, synthesis, and biological evaluation of pyranone-carbamate hybrids as selective butyrylcholinesterase inhibitors with anti-neuroinflammatory activity for Alzheimer's disease

  • Bioorg Chem. 2026 Jul 15:176:109887. doi: 10.1016/j.bioorg.2026.109887.
Xueyan Liu  1 ,  Jiexin Xu  2 ,  Chen Lin  2 ,  Xuan Gao  2 ,  Yuchong Xie  3 ,  Xili Chen  3 ,  Qiaojun Huang  3 ,  Rujing Ye  3 ,  Hang Shi  3 ,  Liangliang Zhang  4 ,  Zu-Cheng Ye  5 ,  Cuimin Wu  6 ,  Daijun Zha  7
Affiliations
  • 1. School of Pharmacy, Fujian Medical University, Fuzhou 350112, Fujian Province, China; Fujian Provincial Key Laboratory of Brain Aging and Neurodegenerative Diseases, The School of Basic Medical Sciences, Fujian Medical University, Fuzhou 350112, Fujian Province, China.
  • 2. School of Pharmacy, Fujian Medical University, Fuzhou 350112, Fujian Province, China.
  • 3. Fujian Provincial Key Laboratory of Brain Aging and Neurodegenerative Diseases, The School of Basic Medical Sciences, Fujian Medical University, Fuzhou 350112, Fujian Province, China.
  • 4. State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), Guangxi Normal University, Guilin 541004, China.
  • 5. Fujian Provincial Key Laboratory of Brain Aging and Neurodegenerative Diseases, The School of Basic Medical Sciences, Fujian Medical University, Fuzhou 350112, Fujian Province, China. Electronic address: [email protected].
  • 6. School of Pharmacy, Fujian Medical University, Fuzhou 350112, Fujian Province, China. Electronic address: [email protected].
  • 7. School of Pharmacy, Fujian Medical University, Fuzhou 350112, Fujian Province, China. Electronic address: [email protected].
PMID: 42008868 DOI: 10.1016/j.bioorg.2026.109887
Abstract

Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder in which cholinergic dysfunction and chronic neuroinflammation jointly contribute to cognitive decline. To address these converging pathological features, a series of carbamate-pyranone hybrids (E1-E17) were designed using a pharmacophore hybridization strategy that integrates the cholinesterase-inhibitory carbamate motif of Rivastigmine with the anti-neuroinflammatory γ-pyranone scaffold derived from D30. Among these derivatives, E14 emerged as a promising hit compound. E14 inhibited lipopolysaccharide-induced nitric oxide production in BV2 microglial cells (IC₅₀ = 9.76 ± 0.59 μM), while maintaining acceptable cytocompatibility. Enzymatic assays revealed that E14 selectively inhibited butyrylcholinesterase, with IC₅₀ values of 15.59 ± 2.98 μM against eqBuChE and 38.65 ± 3.40 μM against hBuChE, while showing negligible activity against acetylcholinesterase, and kinetic analysis indicated a competitive inhibition mechanism. Consistent with its CNS-oriented design, E14 exhibited high passive blood-brain barrier permeability in a PAMPA-BBB assay (Pe = 11.87 × 10-6 cm/s) and showed good acute tolerability in mice. In an oligomeric Aβ-induced cognitive impairment mouse model, E14 significantly improved recognition memory and spatial learning performance. Mechanistic investigations demonstrated that E14 attenuated hippocampal glial activation and neuroinflammation, suppressing the TLR4/p38 MAPK signaling pathway and modulating the IL-1β/C3-mediated microglia-astrocyte inflammatory axis. Network pharmacology analyses further suggested multitarget engagement across inflammation- and stress-related pathways relevant to AD pathology. Collectively, these findings identify E14 as a brain-penetrant, BuChE-selective dual-functional compound that integrates cholinesterase inhibition with anti-neuroinflammatory activity, supporting its further development as a multitarget-directed lead for AD intervention.

Keywords
Alzheimer's disease; Blood–brain barrier permeability; BuChE inhibitors; Multitarget agents; Neuroinflammation.
Products