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Solid-phase Synthesis of [4.4] Spirocyclic Oximes
Published on: February 6, 2019
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Imidazolylacetophenone oxime-based multifunctional neuroprotective agents: Discovery and structure-activity
Bo Ren1, Cong Guo1, Run-Ze Liu1
1Shaanxi Key Laboratory of Natural Products & Chemical Biology, College of Chemistry & Pharmacy, Northwest A&F University, 3 Taicheng Road, Yangling, 712100, Shaanxi, PR China.
European Journal of Medicinal Chemistry
|December 7, 2021
Summary
Novel imidazolylacetophenone oxime ether derivatives show promise as multi-target agents for Alzheimer's disease (AD). These compounds offer neuroprotection through anti-neuroinflammatory and antioxidative effects, potentially treating AD effectively.
Area of Science:
- Medicinal Chemistry
- Neuroscience
- Pharmacology
Background:
- Alzheimer's disease (AD) pathogenesis is complex, necessitating multitarget therapeutic strategies.
- Current research focuses on agents that modulate multiple pathways simultaneously for effective AD treatment.
Purpose of the Study:
- To discover novel multitarget agents for Alzheimer's disease (AD) based on neuroinflammation screening.
- To synthesize and evaluate imidazolylacetophenone oxime ether derivatives for neuroprotective properties.
Main Methods:
- Screening of approximately 1400 compounds identified a novel hit: imidazolylacetophenone oxime ether (IOE).
- Synthesis of IOE derivatives, confirmation of Z-configuration, and evaluation of neuroprotective effects (anti-neuroinflammatory, antioxidative, metal-chelating, AChE inhibition).
- Assays included nitric oxide (NO) production, iNOS, COX-2, HO-1 expression, H2O2-induced PC12 cell damage, ferroptosis, metal chelation, AChE inhibition, and blood-brain barrier (BBB) penetration (PAMPA).
Main Results:
- Compound 12i demonstrated potent inhibition of NO production (EC50 = 0.57 μM) and suppressed iNOS and COX-2 expression.
- 12i provided neuroprotection against H2O2-induced PC12 cell damage and ferroptosis without cytotoxicity, and selectively chelated Cu2+.
- Structure-activity relationship analysis indicated that dioxolane groups and rigid oxime esters enhance activity; 12i showed mixed-type AChE inhibition and BBB permeability.
Conclusions:
- Imidazolylacetophenone oxime derivatives exhibit multifunctional neuroprotective effects, including anti-neuroinflammatory, antioxidative, metal-chelating, and AChE inhibitory properties.
- Compound 12i is a promising lead candidate for developing novel multitarget agents against Alzheimer's disease.
- This study represents the first report of imidazolylacetophenone oxime-based compounds with broad neuroprotective activities relevant to AD therapy.
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