Karim_2023_ACS.Omega_8_8052

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 microM and BuChE with IC(50) values of 80, 50, and 11 microM, 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 microM, 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.