Antiamnesic Effects of Novel Phthalimide Derivatives in Scopolamine-Induced Memory Impairment in Mice: A Useful Therapy for Alzheimer’s Disease

[Image: see text] Phthalimides have diverse bioactivities and are attractive molecules for drug discovery and development. Here, we explored new synthesized phthalimide derivatives (compounds 1–3) in improving memory impairment associated with Alzheimer’s disease (AD), using in vitro and ex vivo acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibition and in vivo models, including Y-maze test and novel object recognition test (NORT). Compounds 1–3 exhibited significant AChE activity with IC(50) values of 10, 140, and 18 μM and BuChE with IC(50) values of 80, 50, and 11 μM, respectively. All compounds 1–3 showed excellent antioxidant potential in DPPH and ABTS assays with IC(50) values in the range of 105–340 and 205–350 μM, respectively. In ex vivo studies, compounds 1–3 also significantly inhibited both enzymes in a concentration-dependent manner along with significant antioxidant activities. In in vivo studies, compounds 1–3 reversed scopolamine-induced amnesia as indicated by a significant increase in the spontaneous alternation in the Y-maze test and an increase in the discrimination index in the NORT. Molecular docking was also conducted for compounds 1–3 against AChE and BuChE, which showed that compounds 1 and 3 have excellent binding with AChE and BuChE as compared to 2. These findings suggest that compounds 1–3 possess significant antiamnesic potential and may serve as useful leads to develop novel therapeutics for the symptomatic management and treatment of AD.