Drug reposition-based design, synthesis, and biological evaluation of dual inhibitors of acetylcholinesterase and β-Secretase for treatment of Alzheimer's disease.

• In-silico based virtual screening of a library (Drug Central Database) containing 4199 FDA approved drugs; MM/GBSA and MD simulation analysis were performed. • Novel structurally modified propamidine derivatives were synthesized, characterized and tested for their anti-AD activity. • Compound 27 was a well-balanced and promising multi-targeting agent. • Compound 27 exhibited good self and AChE-induced Aβ aggregation inhibition in thioflavin T assay. • Compound 27 displayed significant improvement in cognitive dysfunctions against scopolamine-induced amnesia mouse models. The use of multifunctional agents could act as a crucial strategy in the management of neurodegenerative disorders like Alzheimer's disease (AD). In search of multitargeted directed ligands for the treatment of AD, a drug repositioning study has been performed using In silico tools. Virtual screening of a library (Drug Central Database) containing 4199 FDA-approved drugs was utilized for the purpose, and denopamine, guanethidine, and propamidine were identified as hits to target both acetylcholinesterase (AChE) and β-secretase (BACE-1). Further, MM/GBSA and MD simulation analysis was also performed which suggested that propamidine, an antibacterial and antifungal drug , may become a crucial pharmacophore to design multi-target directed ligands for AD therapy. Finally, a series of structurally modified derivatives of propamidine by replacement of terminal amidines with substituted benzamide and acetamide moiety on both ends were synthesized, characterized, and tested for their anti-AD action. Compound 27 of the structurally modified series of propamidine has shown significant in vitro hAChE and hBACE-1 inhibition at submicromolar concentration range (hAChE: IC 50 = 0.832 ± 0.05 µM and hBACE-1: IC 50 = 0.428 ± 0.036 µM). Compounds 27 has also shown significant propidium iodide displacement from the PAS binding region and exhibited good self and AChE-induced Amyloid-β (Aβ) aggregation inhibition in thioflavin T assay. The in-vivo behavioral studies of compound 27 displayed significant improvement in cognitive dysfunctions against scopolamine-induced amnesia mouse models. [Display omitted] [ABSTRACT FROM AUTHOR]