title: Pyridoxine-resveratrol hybrids Mannich base derivatives as novel dual inhibitors of AChE and MAO-B with antioxidant and metal-chelating properties for the treatment of Alzheimer's disease.
abstract: A series of pyridoxine-resveratrol hybrids Mannich base derivatives as multifunctional agents have been designed, synthesized and evaluated for cholinesterase (ChE) and monoamine oxidase (MAO) inhibitory activity. To further explore the multifunctional properties of the new derivatives, their antioxidant activities and metal-chelating properties were also tested. The results showed that most of these compounds could selectively inhibit acetylcholinesterase (AChE) and MAO-B. Among them, compounds 7d and 8b exhibited the highest potency for AChE inhibition with IC50values of 2.11μM and 1.56μM, respectively, and compound 7e exhibited the highest MAO-B inhibition with an IC50value of 2.68μM. The inhibition kinetic analysis revealed that compound 7d showed a mixed-type inhibition, binding simultaneously to the CAS and PAS of AChE. Molecular modeling study was also performed to investigate the binding mode of these hybrids with MAO-B. In addition, all target compounds displayed good antioxidant and metal-chelating properties. Taken together, these preliminary findings can be a new starting point for further development of multifunctional agents for Alzheimer's disease.
authors.affiliation: Department of Medicinal Chemistry, Key Laboratory of Drug Targeting and Drug Delivery System of the Education Ministry, West China School of Pharmacy, Sichuan University, Chengdu 610041, China.
authors.forename: Xia
authors.initials: X
authors.lastname: Yang
authors.affiliation: Department of Medicinal Chemistry, Key Laboratory of Drug Targeting and Drug Delivery System of the Education Ministry, West China School of Pharmacy, Sichuan University, Chengdu 610041, China.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Qiang
authors.affiliation: Department of Medicinal Chemistry, Key Laboratory of Drug Targeting and Drug Delivery System of the Education Ministry, West China School of Pharmacy, Sichuan University, Chengdu 610041, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Medicinal Chemistry, Key Laboratory of Drug Targeting and Drug Delivery System of the Education Ministry, West China School of Pharmacy, Sichuan University, Chengdu 610041, China.
authors.forename: Li
authors.initials: L
authors.lastname: Luo
authors.affiliation: Department of Medicinal Chemistry, Key Laboratory of Drug Targeting and Drug Delivery System of the Education Ministry, West China School of Pharmacy, Sichuan University, Chengdu 610041, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Xu
authors.affiliation: Department of Medicinal Chemistry, Key Laboratory of Drug Targeting and Drug Delivery System of the Education Ministry, West China School of Pharmacy, Sichuan University, Chengdu 610041, China.
authors.forename: Yunxiaozhu
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Department of Medicinal Chemistry, Key Laboratory of Drug Targeting and Drug Delivery System of the Education Ministry, West China School of Pharmacy, Sichuan University, Chengdu 610041, China.
authors.forename: Zhongcheng
authors.initials: Z
authors.lastname: Cao
authors.affiliation: Institute of Traditional Chinese Medicine Pharmacology and Toxicology, Sichuan Academy of Chinese Medicine Sciences, Chengdu 610041, China. Electronic address: tanzhh616@163.com.
authors.forename: Zhenghuai
authors.initials: Z
authors.lastname: Tan
authors.affiliation: Department of Medicinal Chemistry, Key Laboratory of Drug Targeting and Drug Delivery System of the Education Ministry, West China School of Pharmacy, Sichuan University, Chengdu 610041, China. Electronic address: dengyong@scu.edu.cn.
authors.forename: Yong
authors.initials: Y
authors.lastname: Deng
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism; D000544:Alzheimer Disease / Q000188:drug therapy / Q000201:enzymology; D000818:Animals; D000975:Antioxidants / Q000737:chemistry / Q000494:pharmacology*; D002614:Chelating Agents / Q000737:chemistry / Q000494:pharmacology*; D002800:Cholinesterase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D004593:Electrophorus; D006801:Humans; D007700:Kinetics; D008352:Mannich Bases / Q000737:chemistry / Q000494:pharmacology; D008670:Metals / Q000378:metabolism; D008958:Models, Molecular; D008995:Monoamine Oxidase / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D011736:Pyridoxine / Q000031:analogs & derivatives / Q000494:pharmacology*; D051381:Rats; D000077185:Resveratrol; D013267:Stilbenes / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000975:Antioxidants; D002614:Chelating Agents; D002800:Cholinesterase Inhibitors; D008352:Mannich Bases; D008670:Metals; D008996:Monoamine Oxidase Inhibitors; D013267:Stilbenes; D008995:Monoamine Oxidase; D000110:Acetylcholinesterase; D011736:Pyridoxine; D000077185:Resveratrol
keywords: AChE inhibitors; Alzheimer’s disease; Antioxidant; MAO-B inhibitors; Mannich base derivatives; Metal-chelating; Pyridoxine-Resveratrol hybrids