Design, synthesis, and preclinical evaluation of novel 1-benzylpiperidine derivatives as multitarget agents against Alzheimer's disease.

Small molecules targeting pathologies of Alzheimer's disease (AD) is a promising approach. Identification of potential molecules using computational techniques and their synthesis provides potential applications in the treatment of AD. 2D fingerprint similarity screening, using the Tanimoto coefficient, identified structurally similar molecules to donepezil for lead identification. A molecule with a Tanimoto coefficient of 0.7 was chosen, and derivatives were synthesized. In silico screening of the synthesized compounds indicated strong binding to acetylcholinesterase (AChE). All molecules met drug-likeness criteria and showed 100 % oral absorption. Key interactions with AChE were observed, crucial for inhibitory activity. Molecular dynamics simulations over 100 ns showed stable binding conformations. In vitro assays for AChE and amyloid β (Aβ) inhibition were conducted after the cytotoxicity testing in microglial cells for all four synthesized compounds. Among the tested compounds at 5 μM, (E)-2-(((1-benzylpiperidin-4-yl)imino)methyl)-4-methylphenol (5MeSA4ABP) with AChE (57.46 ± 2.140 %) and Aβ inhibition (57.83 ± 0.08 %), was selected for lipopolysaccharide-induced AD-like mouse model. Behavioural analysis using Morris water maze and open field tests revealed memory impairment in mice. Brain estimations were performed to study the effect of treatments on AD markers such as interleukin-6 (IL-6), Aβ and AChE. In mice with AD pathology, oral administration of 5MeSA4ABP resulted in improved cognitive function without any impact on locomotor activity. Except brain AChE activity, treatment with 5MeSA4ABP significantly reversed the elevated brain IL-6 and Aβ levels. Thus, synthesized hybrid pharmacophores, 5MeSA4ABP, exert its activity via reducing neuroinflammation and plaque deposition. Future investigation are warranted for safety and efficacy mechanisms of 5MeSA4ABP against AD.