Synthesis and characterization of 1H-phenanthro[9,10-d]imidazole derivatives as multifunctional agents for treatment of Alzheimer's disease

• Published in: Biochimica et biophysica acta Vol. 1840; no. 9; pp. 2886 - 2903
• Main Authors: Liu, Jinggong, Qiu, Jun, Wang, Mingxue, Wang, Ling, Su, Lijuan, Gao, Jinbo, Gu, Qiong, Xu, Jun, Huang, Shi-Liang, Gu, Lian-Quan, Huang, Zhi-Shu, Li, Ding
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.09.2014
• Subjects: acetylcholine; acetylcholinesterase; Acetylcholinesterase - metabolism; Alzheimer disease; Alzheimer Disease - drug therapy; Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Alzheimer's disease; Amyloid beta-Peptides - metabolism; Anti-oxidation; Antioxidants - chemical synthesis; Antioxidants - chemistry; Antioxidants - pharmacology; Aβ aggregation; brain; Cell Line, Tumor; Cholinesterase; copper; gel electrophoresis; Humans; Imidazole derivative; Imidazoles - chemical synthesis; Imidazoles - chemistry; Imidazoles - pharmacology; inhibitory concentration 50; iron; memory; Molecular Docking Simulation; molecular models; oxygen radical absorbance capacity; Peptide Fragments - metabolism; Phenanthrenes - chemical synthesis; Phenanthrenes - chemistry; Phenanthrenes - pharmacology; transmission electron microscopy; Western blotting; MTDLs; ThT; PAS; AAPH; Aβ aggregation; TLC; MTT; Anti-oxidation; Aβ; DMEM; BuChE; Alzheimer's disease; ORAC; AChE; ChE; AD; DTNB; RMSD; Cholinesterase; ATC; BTC; DCFH-DA; CAS; Imidazole derivative; ROS; TEM
• ISSN: 0304-4165; 0006-3002; 1872-8006
• DOI: 10.1016/j.bbagen.2014.05.005

Alzheimer's disease (AD) is a progressive neurodegenerative brain disorder that is characterized by dementia, cognitive impairment, and memory loss. Diverse factors are related to the development of AD, such as increased level of β-amyloid (Aβ), acetylcholine, metal ion deregulation, hyperphosphorylated tau protein, and oxidative stress. The following methods were used: organic syntheses of 1H-phenanthro[9,10-d]imidazole derivatives, inhibition of self-mediated and metal-induced Aβ1–42 aggregation, inhibition studies for acetylcholinesterase and butyrylcholinesterase, anti-oxidation activity studies, CD, MTT assay, transmission electron microscopy, dot plot assay, gel electrophoresis, Western blot, and molecular docking studies. We synthesized and characterized a new type of 1H-phenanthro[9,10-d]imidazole derivatives as multifunctional agents for AD treatment. Our results showed that most of these derivatives exhibited strong Aβ aggregation inhibitory activity. Compound 9g had 74% Aβ1–42 aggregation inhibitory effect at 10μM concentration with its IC50 value of 6.5μM for self-induced Aβ1–42 aggregation. This compound also showed good inhibition of metal-mediated (Cu2+ and Fe2+) and acetylcholinesterase-induced Aβ1–42 aggregation, as indicated by using thioflavin T assay, transmission electron microscopy, gel electrophoresis, and Western blot. Besides, compound 9g exhibited cholinesterase inhibitory activity, with its IC50 values of 0.86μM and 0.51μM for acetylcholinesterase and butyrylcholinesterase, respectively. In addition, compound 9g showed good anti-oxidation effect with oxygen radical absorbance capacity (ORAC) value of 2.29. Compound 9g was found to be a potent multi-target-directed agent for Alzheimer's disease. Compound 9g could become a lead compound for further development as a multi-target-directed agent for AD treatment. •We synthesized a new type of 1H-phenanthro[9,10-d]imidazole derivatives.•Among these derivatives, compound 9g showed strong Aβ aggregation inhibitory activity.•Compound 9g also exhibited cholinesterase inhibitory activity.•Compound 9g also showed good anti-oxidation effect.•Compound 9g is a multifunctional lead compound for Alzheimer's disease treatment.