Design, Synthesis, and Evaluation of Donepezil-Like Compounds as AChE and BACE-1 Inhibitors

Abstract

An ecofriendly synthetic pathway for the synthesis of donepezil precursors is described. Alternative energy sources were used for the total synthesis in order to improve yields, regioselectively, and rate of each synthetic step and to reduce the coproduction of waste at the same time. For all products, characterized by an improved structural rigidity respect to donepezil, the inhibitor activity on AChE, the selectivity vs BuChE, the side-activity on BACE-1, and the effect on SHSY-5Y neuroblastoma cells viability were tested. Two potential new lead compounds for a dual therapeutic strategy against Alzheimer's disease were envisaged.

Donepezil: A review of the recent structural modifications and their impact on anti-Alzheimer activity

“…Various structural modifications of this drug have been carried out and they are described in the following sections. Costanzo et al (2016) carried out the synthesis of donepezil derivatives in which benzylpiperidine and indanone part were connected through the double bond. Compounds 2 ( Figure 2) and 3 showed the most active inhibition of human erythrocytes AChE having IC 50 values of 0.058 ± 0.033 μM and 0.043 ± 0.007 μM respectively.…”

“…Compounds 2 ( Figure 2) and 3 showed the most active inhibition of human erythrocytes AChE having IC 50 values of 0.058 ± 0.033 μM and 0.043 ± 0.007 μM respectively. These compounds were found to be selective for AChE as compared to butyrylcholinesterase (BuChE) with selectivity values of 81 and 132 for compounds 2 and 3 respectively (Costanzo et al, 2016). Azzouz et al synthesized bioxidiazable prodrugs of donepezil in which N-benzylpyridinium quaternary amine fragment was attached to indanone, tetralone and acetophenone fragments.…”

Design, Synthesis and Biological Assessment of Novel 2‐(4‐Alkoxybenzylidine)‐2,3‐dihydro‐5,6‐dimethoxy‐1H‐inden‐1‐one Derivatives as hAChE and hBuChE Enzyme Inhibitors

“…Alzheimer's disease (AD) is a progressive neurodegenerative disorder with a selective loss of cholinergic neurons of the central nervous system (CNS) and decreasing levels of acetylcholine (ACh) . At the moment, AD affects over 20 million people all around the world and increases with growth in the aging population; as expected to be double in 20 years .…”

Synthesis, Antioxidant Activity, Acetylcholinesterase Inhibition and Quantum Studies of Thiosemicarbazones

“…13 AD is a progressive neurodegenerative disorder of the central nervous system characterized by mental deterioration. 14 The disease is not completely understood, different hypotheses try to explain its causes and form the basis of current therapies. 15 Treatment strategies employ the use of acetylcholinesterase inhibitors, glutamate receptor modulators, and antioxidants and anti-inflammatory agents.…”