title: New multifunctional melatonin-derived benzylpyridinium bromides with potent cholinergic, antioxidant, and neuroprotective properties as innovative drugs for Alzheimer's disease.
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.
authors.affiliation: Department of Pharmacy, 1st Affiliated Hospital of Guangxi Medical University, Nanning, 530021, China.
authors.forename: Xiao-Ting
authors.initials: XT
authors.lastname: Luo
authors.affiliation: Department of Ordinary Intervention, People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, 530000, China.
authors.forename: Chun-Ming
authors.initials: CM
authors.lastname: Wang
authors.affiliation: Division of Spinal Surgery, 1st Affiliated Hospital of Guangxi Medical University, Nanning, 530021, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Pharmacy, 1st Affiliated Hospital of Guangxi Medical University, Nanning, 530021, China. Electronic address: gzhuangzhenguang@163.com.
authors.forename: Zhen-Guang
authors.initials: ZG
authors.lastname: Huang
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000473:pathology; D000975:Antioxidants / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002802:Cholinesterases / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D008550:Melatonin / Q000737:chemistry*; D008958:Models, Molecular; D015394:Molecular Structure; D009447:Neuroblastoma / Q000188:drug therapy* / Q000473:pathology; D018696:Neuroprotective Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011726:Pyridinium Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: C000607135:1-(3-fluorobenzyl)-4-(3-((2-(5-methoxy-1H-indol-3-yl)ethyl)amino)-3-oxoprop-1-en-1-yl)pyridin-1-ium; D000975:Antioxidants; D002800:Cholinesterase Inhibitors; D007211:Indoles; D018696:Neuroprotective Agents; D011726:Pyridinium Compounds; D002802:Cholinesterases; D008550:Melatonin
keywords: Alzheimer's disease; Antioxidant; Benzylpyridinium; Cholinesterase; Melatonin; Neuroprotection