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Abstract The multitarget-directed strategy offers an effective and promising paradigm to treat the complex neurodegenerative disorder, such as Alzheimer's disease (AD). Herein, a series of N -benzylpiperidine analogs (17 – 31 and 32 – 46) were designed and synthesized as multi-functional inhibitors of acetylcholinesterase (AChE) and β-secretase-1 (BACE-1) with moderate to excellent inhibitory activities. Among the tested inhibitors, 25, 26, 40, and 41 presented the most significant and balanced inhibition against both the targets. Compounds 40 and 41 exhibited high brain permeability in the PAMPA-BBB assay, significant displacement of propidium iodide from the peripheral anionic site (PAS) of AChE, and were devoid of neurotoxicity towards SH-SY5Y neuroblastoma cell lines up to the maximum tested concentration of 80 μM. Meanwhile, both these compounds inhibited self- and AChE-induced Aβ aggregation in thioflavin T assay, which was also re-affirmed by morphological characterization of Aβ aggregates using atomic force microscopy (AFM). Moreover, 40 and 41 ameliorated the scopolamine-induced cognitive impairment in elevated plus and Y-maze experiments. Ex vivo and biochemical analysis established the brain AChE inhibitory potential and antioxidant properties of these compounds. Further, improvement in Aβ 1-42 -induced cognitive impairment was also observed by compound 41 in the Morris water maze experiment with significant oral absorption characteristics ascertained by the pharmacokinetic studies. Graphical abstract Image 1 Highlights • Design and synthesis of a series of N -benzylpiperidine analogs (17 – 46). • Compounds 25, 26, 40, and 41 exhibited balanced inhibition of AChE and BACE-1. • Propidium iodide displacement and inhibition of Aβ aggregation by 40 and 41. • Biochemical analysis of rat brain homogenates suggested antioxidant potential. • Amelioration of scopolamine- and Aβ-induced cognitive impairment in AD rat models. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Novel p-aminobenzoic acid derivatives were designed, synthesized and characterized. • The compounds exhibited significant inhibitory potential against AChE and BChE. • Compound 22 exhibited significant improvements in working and reference memory. • The ex vivo study confirmed the ability of compound 22 to cross the BBB. • The in silico studies demonstrated the binding to active pocket in a stable manner. Abstract Based on the quantitative structure-activity relationship (QSAR), some novel p-aminobenzoic acid derivatives as promising cholinesterase enzyme inhibitors were designed, synthesized, characterized and evaluated to enhance learning and memory. The in vitro enzyme kinetic study of the synthesized compounds revealed the type of inhibition on the respective acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes. The in vivo studies of the synthesized compounds exhibited significant reversal of cognitive deficits in the animal models of amnesia as compared to standard drug donepezil. Further, the ex vivo studies in the specific brain regions like the hippocampus, hypothalamus, and prefrontal cortex regions also exhibited AChE inhibition comparable to standard donepezil. The in silico molecular docking and dynamics simulations studies of the most potent compound 22 revealed the consensual interactions at the active site pocket of the AChE. [ABSTRACT FROM AUTHOR]