title: Synthesis and pharmacological evaluation of multifunctional tacrine derivatives against several disease pathways of AD.
abstract: A novel series of tacrine derivatives were designed and synthesized by combining caffeic acid (CA), ferulic acid (FA) and lipoic acid (LA) with tacrine. The antioxidant study revealed that all the hybrids have much more antioxidant capacities compared to CA. Among these compounds, 1b possessed a good ability to inhibit the β-amyloid protein (Aβ) self-aggregation, sub-micromole acetylcholinesterase (AChE)/butyrylcholinesterase (BuChE) inhibitory, modest BACE1 inhibitory. Moreover, compound 1b also was a DPPH radical scavenger and copper chelatory as well as had potent neuroprotective effects against glutamate-induced cell death with low toxicity in HT22 cells. Our findings suggest that the compound 1b might be a promising lead multi-targeted ligand and worthy of further developing for the therapy of Alzheimer's disease.
authors.affiliation: Dipartimento di Farmacia, Università di Pisa, Via Bonanno, 656126 Pisa, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Digiacomo
authors.affiliation: Department of Pharmacology & Toxicology, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China; International Joint Laboratory (SYSU-PolyU HK) of Novel Anti-Dementia Drugs of Guangdong, Guangzhou 510006, China.
authors.forename: Ziwei
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Department of Pharmacology & Toxicology, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China; International Joint Laboratory (SYSU-PolyU HK) of Novel Anti-Dementia Drugs of Guangdong, Guangzhou 510006, China.
authors.forename: Shengnan
authors.initials: S
authors.lastname: Wang
authors.affiliation: Dipartimento di Farmacia, Università di Pisa, Via Bonanno, 656126 Pisa, Italy.
authors.forename: Annalina
authors.initials: A
authors.lastname: Lapucci
authors.affiliation: Dipartimento di Farmacia, Università di Pisa, Via Bonanno, 656126 Pisa, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Macchia
authors.affiliation: Department of Pharmacology & Toxicology, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China; International Joint Laboratory (SYSU-PolyU HK) of Novel Anti-Dementia Drugs of Guangdong, Guangzhou 510006, China.
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Yang
authors.affiliation: Department of Pharmacology & Toxicology, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China; International Joint Laboratory (SYSU-PolyU HK) of Novel Anti-Dementia Drugs of Guangdong, Guangzhou 510006, China.
authors.forename: Jiaqi
authors.initials: J
authors.lastname: Chu
authors.affiliation: International Joint Laboratory (SYSU-PolyU HK) of Novel Anti-Dementia Drugs of Guangdong, Guangzhou 510006, China; Department of Applied Biology and Chemical Technology, Institute of Modern Chinese Medicine, The Hong Kong Polytechnic University, Hung Hom, Hong Kong, China.
authors.forename: Yifan
authors.initials: Y
authors.lastname: Han
authors.affiliation: Department of Pharmacology & Toxicology, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China; International Joint Laboratory (SYSU-PolyU HK) of Novel Anti-Dementia Drugs of Guangdong, Guangzhou 510006, China. Electronic address: pirb@mail.sysu.edu.cn.
authors.forename: Rongbiao
authors.initials: R
authors.lastname: Pi
authors.affiliation: Dipartimento di Farmacia, Università di Pisa, Via Bonanno, 656126 Pisa, Italy. Electronic address: simona.rapposelli@farm.unipi.it.
authors.forename: Simona
authors.initials: S
authors.lastname: Rapposelli
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000378:metabolism; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors / Q000378:metabolism; D002109:Caffeic Acids / Q000737:chemistry; D002460:Cell Line; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D003373:Coumaric Acids / Q000737:chemistry; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D013329:Structure-Activity Relationship; D013619:Tacrine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*; D008063:Thioctic Acid / Q000737:chemistry
chemical_list: D016229:Amyloid beta-Peptides; D002109:Caffeic Acids; D002800:Cholinesterase Inhibitors; D003373:Coumaric Acids; D013619:Tacrine; D008063:Thioctic Acid; C004999:ferulic acid; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; C040048:caffeic acid
keywords: Alzheimer’s disease; Amyloid protein; BACE1; Caffeic acid; Copper; Multi-targeted ligands; Tacrine