Design, synthesis, and evaluation of some novel biphenyl imidazole derivatives for the treatment of Alzheimer's disease.

• Novel 4, 5-diphenyl-1 H -imidazole linked piperazine hybrids were rationally designed. • Compound 6f was a well-balanced and promising multi-targeting agent. • Compound 6f showed good propidium iodide displacement. • compound 6f (10 mg/kg) showed a statistically non-significant difference in % spontaneous alterations The multi-targeted organized strategy provides effectual and significant results to cure progressive neurodegenerative diseases like AD. Treatment for this awful disease is in infancy till now. A series of novel 4, 5-diphenyl-1 H -imidazole linked piperazine hybrids (6a-g and 7a-g) were synthesized by utilizing the concept of bio-isosteric replacement and hybrid pharmacophore approaches. The targeted compounds were identified by spectroscopic techniques and assessed for in vitro cholinesterase, BACE-1 inhibition, propidium iodide displacement, and Aβ disaggregation activities. Within the targeted inhibitors, 6f exhibited the most significant and inhibitory capacity against eeAChE (IC 50 = 0.416 ± 0.018 μM), eqBChE (IC 50 = 0.474 ± 0.054 μM), and BACE-1 (IC 50 = 0.392 ± 0.021 μM) targets. Propidium iodide displacement showed that compound 6f could be effectively linked with AChE's PAS (10 μM = 29.09 %, 50 μM = 41.43%). It showed inhibitory potential against both self (21.28 to 30.85%) and AChE-induced (25.70 to 51.07%) Aβ aggregation in thioflavin T assay. Moreover, the most active compound 6f was evaluated by performing in vivo behavioural studies with the help of the scopolamine-induced Y-maze model. The in vitro and in vivo in collaboration with in silico molecular docking and molecular dynamics simulation leads to ascertain the active site interaction of compound 6f with AChE and BACE-1. [ABSTRACT FROM AUTHOR]