1. New multifunctional melatonin-derived benzylpyridinium bromides with potent cholinergic, antioxidant, and neuroprotective properties as innovative drugs for Alzheimer's disease
- Author
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Yun Liu, Zhen-Guang Huang, Xiao-Ting Luo, and Chun-Ming Wang
- Subjects
Models, Molecular ,Indoles ,Antioxidant ,Aché ,medicine.medical_treatment ,Pyridinium Compounds ,Pharmacology ,Neuroprotection ,Antioxidants ,Melatonin ,Neuroblastoma ,Structure-Activity Relationship ,chemistry.chemical_compound ,Alzheimer Disease ,Cell Line, Tumor ,Drug Discovery ,medicine ,Cholinesterases ,Humans ,Structure–activity relationship ,Cholinesterase ,Dose-Response Relationship, Drug ,Molecular Structure ,biology ,Chemistry ,Organic Chemistry ,General Medicine ,language.human_language ,In vitro ,Neuroprotective Agents ,Biochemistry ,Drug Design ,language ,biology.protein ,Cholinesterase Inhibitors ,Trolox ,medicine.drug - Abstract
A novel series of melatonin-derived benzylpyridinium bromides have been designed, synthesized, and evaluated as multi-functional anti-AD agents with cholinesterase inhibitory, antioxidant, and neuroprotective activities. In vitro studies showed that most of these compounds exhibited potent inhibitory activity toward h-AChE and h-BuChE, and good antioxidant capacity in the ORAC assay. In particular, compound 19 was the most attractive derivative, showing the highest potency to inhibit ChEs (AChE: IC₅₀ = 0.11 μM; BuChE: IC₅₀ = 1.1 μM) and good antioxidant ability (ORAC (trolox) = 3.41). Kinetic and molecular modeling studies indicated that 19 was a mixed-type inhibitor, binding simultaneously to active and peripheral sites of AChE. Moreover, 19 also showed good neuroprotective effects in human SH-SY5Y neuroblastoma cells. Taken together, these results suggested that compound 19 might be a promising multi-target drug candidate worthy of further pursuit.
- Published
- 2015
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