Design, Synthesis, and Biological Evaluation of a New Series of Biphenyl/Bibenzyl Derivatives Functioning as Dual Inhibitors of Acetylcholinesterase and Butyrylcholinesterase.

Dong-Mei Wang,Hui Fu,Ai-Lin Liu,Guan-Hua Du,Lin Wang,Bo Feng,Song Wu

doi:10.3390/molecules22010172

Abstract

Alzheimer’s disease (AD), the most common form of dementia in adults, is a progressive neurodegenerative disorder of the brain characterized by loss of memory and steady deterioration of cognition. Here, a series of symmetrical molecules containing biphenyl/bibenzyl scaffolds (12–36) were designed, synthesized, and evaluated for their ability to inhibit both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). A biological evaluation showed that most of these biphenyl derivatives were potent AChE and BuChE inhibitors. Among them, compound 15 displayed the greatest ability to inhibit BuChE (IC50 = 0.74 µM) and was also a good AChE inhibitor (IC50 = 1.18 µM). Compound 19 was not only a potent AChE inhibitor (IC50 = 0.096 µM), but also a mild BuChE inhibitor (IC50 =1.25 µM). Overall, these results suggested that compound 19 may be a promising agent in the treatment of AD.

Highlights

Alzheimer’s disease (AD), the most common form of dementia in adults, is a progressive neurodegenerative disorder of the brain characterized by loss of memory and steady deterioration of cognition
Several findings indicate that amyloid-β plaques [2], tau protein aggregation [3], oxidative stress [4,5], and a low level of acetylcholine in the brain play important roles in the pathophysiology of the disease [6]
We found that compound 15 (12–36), compound showed the strongest inhibition against AChE, with an IC50 value of 0.096 μM, exhibited the strongest inhibition against BuChE, with IC50 values of 0.74 μM, which was as potent approximately the potency donepezil μM)

Summary

Introduction

Alzheimer’s disease (AD), the most common form of dementia in adults, is a progressive neurodegenerative disorder of the brain characterized by loss of memory and steady deterioration of cognition. This disease currently affects more than 30 million people worldwide [1]. The exact pathophysiology of AD remains unclear. Several findings indicate that amyloid-β plaques [2], tau protein aggregation [3], oxidative stress [4,5], and a low level of acetylcholine in the brain play important roles in the pathophysiology of the disease [6]. Several research strategies have been envisaged recently, the current therapeutic option is limited to only four AChE inhibitors [7,8], namely, donepezil, rivastigmine, galantamine, and tacrine ( discontinued), and one N-methyl-D-aspartate receptor antagonist, memantine [9]

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