title: Design, synthesis and evaluation of novel tacrine-multialkoxybenzene hybrids as multi-targeted compounds against Alzheimer's disease.
abstract: A series of benzoates (or phenylacetates or cinnamates) - tacrine hybrids (7a-o) were designed, synthesized and evaluated as multi-potent anti-Alzheimer drug candidates. The screening results showed that most of them exhibited a significant ability to inhibit ChEs, certain selectivity for AChE over BuChE and strong potency inhibitory of self-induced β-amyloid (Aβ) aggregation. All IC50 values of biological activity were at the nanomolar range. Especially, compound 7c displayed the greatest ability to inhibit AChE with an IC50 value of 5.63 nM and the highest selectivity with ratio of BuChE/AChE value of 64.6. Moreover, it also exhibited a potent inhibitory of Aβ aggregation with an IC50 value of 51.81 nM. A Lineweaver-Burk plot and molecular modeling study showed that compound 7c targeted both the CAS and PAS of ChEs. A structure-activity relationship analysis suggested that the electron density of aromatic ring which was linked with tacrine through acetyl group played a significant role in determining the inhibitory activity.
authors.affiliation: School of Pharmaceutical Sciences, Guangzhou Medical University, Xinzao, Panyu District, Guangzhou, 511436, PR China. Electronic address: chao-zh@163.com.
authors.forename: Chao
authors.initials: C
authors.lastname: Zhang
authors.affiliation: School of Pharmaceutical Sciences, Guangzhou Medical University, Xinzao, Panyu District, Guangzhou, 511436, PR China.
authors.forename: Qiao-Yi
authors.initials: QY
authors.lastname: Du
authors.affiliation: School of Pharmaceutical Sciences, Guangzhou Medical University, Xinzao, Panyu District, Guangzhou, 511436, PR China.
authors.forename: Lang-Di
authors.initials: LD
authors.lastname: Chen
authors.affiliation: School of Pharmaceutical Sciences, Guangzhou Medical University, Xinzao, Panyu District, Guangzhou, 511436, PR China.
authors.forename: Wen-Hao
authors.initials: WH
authors.lastname: Wu
authors.affiliation: School of Pharmaceutical Sciences, Guangzhou Medical University, Xinzao, Panyu District, Guangzhou, 511436, PR China.
authors.forename: Si-Yan
authors.initials: SY
authors.lastname: Liao
authors.affiliation: School of Pharmaceutical Sciences, Guangzhou Medical University, Xinzao, Panyu District, Guangzhou, 511436, PR China.
authors.forename: Li-Hong
authors.initials: LH
authors.lastname: Yu
authors.affiliation: School of Pharmaceutical Sciences, Guangzhou Medical University, Xinzao, Panyu District, Guangzhou, 511436, PR China.
authors.forename: Xin-Tong
authors.initials: XT
authors.lastname: Liang
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism; D000544:Alzheimer Disease / Q000188:drug therapy*; D016229:Amyloid beta-Peptides / Q000737:chemistry; D000818:Animals; D001554:Benzene / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D002091:Butyrylcholinesterase / Q000378:metabolism; D060326:Chemistry Techniques, Synthetic; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D015195:Drug Design; D007700:Kinetics; D008958:Models, Molecular; D010446:Peptide Fragments / Q000737:chemistry; D055503:Protein Multimerization; D017433:Protein Structure, Secondary / Q000187:drug effects; D013619:Tacrine / Q000737:chemistry*
chemical_list: D016229:Amyloid beta-Peptides; D002800:Cholinesterase Inhibitors; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D013619:Tacrine; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase; D001554:Benzene
keywords: Alzheimer's disease; Cholinesterase inhibitors; Multi-target-directed ligands; Self-induced Aβ aggregation; Tacrine