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

ABSTRACT

BACKGROUND: 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 ß-amyloid (Aß), acetylcholine, metal ion deregulation, hyperphosphorylated tau protein, and oxidative stress. METHODS: The following methods were used organic syntheses of 1H-phenanthro[9,10-d]imidazole derivatives, inhibition of self-mediated and metal-induced Aß1-42 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. RESULTS: 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 Aß aggregation inhibitory activity. Compound 9g had 74% Aß1-42 aggregation inhibitory effect at 10µM concentration with its IC50 value of 6.5µM for self-induced Aß1-42 aggregation. This compound also showed good inhibition of metal-mediated (Cu(2+) and Fe(2+)) and acetylcholinesterase-induced Aß1-42 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. CONCLUSIONS: Compound 9g was found to be a potent multi-target-directed agent for Alzheimer's disease. GENERAL SIGNIFICANCE: Compound 9g could become a lead compound for further development as a multi-target-directed agent for AD treatment.