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 β -amyloid (A β ), acetylcholine, metal ion deregulation, hyperphosphorylated tau protein, and oxidative stress. Methods The following methods were used: organic syntheses of 1 H -phenanthro[9,10- d ]imidazole derivatives, inhibition of self-mediated and metal-induced A β 1–42 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 1 H -phenanthro[9,10- d ]imidazole derivatives as multifunctional agents for AD treatment. Our results showed that most of these derivatives exhibited strong A β aggregation inhibitory activity. Compound 9g had 74% A β 1–42 aggregation inhibitory effect at 10 μM concentration with its IC 50 value of 6.5 μM for self-induced A β 1–42 aggregation. This compound also showed good inhibition of metal-mediated (Cu 2 + and Fe 2 + ) and acetylcholinesterase-induced A β 1–42 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 IC 50 values of 0.86 μM and 0.51 μM 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.