Design, synthesis, in vitro, and in vivo evaluation of novel phthalazinone‐based derivatives as promising acetylcholinesterase inhibitors for treatment of Alzheimer's disease

Abstract

Twenty novel phthalazinone‐based compounds were designed as acetylcholinesterase (hAChE) inhibitors. Compounds 7e and 17c demonstrated comparable or superior activity compared to donepezil, respectively, in in vitro enzyme assay. Moreover, both compounds 7e and 17c possess minimal toxicity on hepatic and neuroblastoma cell lines. Besides, it was proved that compounds 7e and 17c have percentage alternations and a transfer latency time comparable to donepezil and can alleviate the cognitive impairment caused by the scopolamine‐induced model in mice. The kinetic analysis for compound 17c suggested this compound as a mixed‐type inhibitor that could bind to both the peripheral (PAS) and the catalytic site (CAS) of the hAChE enzyme. The synthesized molecules were subjected to in silico analyses, including molecular docking studies, and the outcomes were consistent with the in vitro findings.

Tryptamine: A privileged scaffold for the management of Alzheimer's disease

“…In this hypothesis, a deficiency of a key neurotransmitter (ACh) was observed, due to either reduced production of ACh or amplified activity of acetylcholinesterase (AChE) (Figure 2). AChE is a hydrolytic enzyme that catalyzes the breakdown of ACh into choline and acetate, thereby rapidly terminating cholinergic transmission (Ezzat et al, 2019). Therefore, the inhibition of AChE‐by‐AChE inhibitor is the main target for the management of early and moderate stages of AD (Marucci et al, 2021; G. Singh et al, 2022).…”

Synthesis of thiazole derivatives as cholinesterase inhibitors with antioxidant activity

“…Alzheimer's disease (AD) is the most common neurodegenerative disease at the moment, which causes loss of memory, behavioral problems, and a reduction in cognitive function eventually leading to death [1,2]. The disease is most commonly caused by cholinergic hypothesis, Amyloid-β (Ab) plague formation, N-methyl-D-aspartate (NMDA) receptor (NMDAR) antagonism hypothesis, The accumulation of thin protein after their hyperphosphorylation, biometal dyshomeostasis, and oxidative stress [3][4][5].…”