New Tetrahydroacridine Hybrids with Dichlorobenzoic Acid Moiety Demonstrating Multifunctional Potential for the Treatment of Alzheimer’s Disease

Abstract

A series of new tetrahydroacridine and 3,5-dichlorobenzoic acid hybrids with different spacers were designed, synthesized, and evaluated for their ability to inhibit both cholinesterase enzymes. Compounds 3a, 3b, 3f, and 3g exhibited selective butyrylcholinesterase (EqBuChE) inhibition with IC50 values ranging from 24 to 607 nM. Among them, compound 3b was the most active (IC50 = 24 nM). Additionally, 3c (IC50 for EeAChE = 25 nM and IC50 for EqBuChE = 123 nM) displayed dual cholinesterase inhibitory activity and was the most active compound against acetylcholinesterase (AChE). Active compound 3c was also tested for the ability to inhibit Aβ aggregation. Theoretical physicochemical properties of the compounds were calculated using ACD Labs Percepta and Chemaxon. A Lineweaver–Burk plot and docking study showed that 3c targeted both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE. Moreover, 3c appears to possess neuroprotective activity and could be considered a free-radical scavenger. In addition, 3c did not cause DNA damage and was found to be less toxic than tacrine after oral administration; it also demonstrated little inhibitory activity towards hyaluronidase (HYAL), which may indicate that it possesses anti-inflammatory properties. The screening for new in vivo interactions between 3c and known receptors was realized by yeast three-hybrid technology (Y3H).

Novel Cyclopentaquinoline and Acridine Analogs as Multifunctional, Potent Drug Candidates in Alzheimer’s Disease

“…Our investigation of the novel derivatives included the inhibition potency against AChE and BuChE, kinetic studies, and an evaluation of antioxidant activity and toxicity. The inhibition studies against AChE and BuChE were performed using a modified version of Ellman’s method [ 29 , 34 ].…”

“…An evaluation of the inhibitory potency towards AChE (EC 3.1.1.7, Electrophorus electricus ) and BuChE (EC 3.1.1.8, equine serum) was performed using a modified spectrophotometric Ellman’s method [ 29 , 34 ]. All necessary reagents for the study were purchased from Sigma Aldrich (Steinheim, Germany).…”

The Tao Hong Si Wu Decoction ameliorates diabetes‐associated cognitive dysfunction by inhibiting the formation of amyloid plaques

“…14,15 β-secretase (BACE1) and γ-secretase cleave their amyloid precursor protein (APP) to produce Aβ. 16 Aβ exists mainly in two main forms which are Aβ 1−40 and Aβ 1−42 . They had significant neurotoxicity and were also hallmark predictor of Alzheimer's disease (AD) disease.…”

“…The amount of Aβ deposited in the hippocampus can directly affect the cognitive ability of rats 14,15 . β‐secretase (BACE1) and γ‐secretase cleave their amyloid precursor protein (APP) to produce Aβ 16 . Aβ exists mainly in two main forms which are Aβ 1−40 and Aβ 1−42 .…”

New cyclopentaquinoline and 3,5-dichlorobenzoic acid hybrids with neuroprotection against oxidative stress for the treatment of Alzheimer’s disease

“…The obtained results for 3,5-dichlorobenzoic acid derivatives inspired us to expand the syntheses and the scope of research for these promising hybrids. In this way, developed this group of molecules (presented in this publication) and design new structures cyclopentaquinoline that have never been published 36 . We elaborated new therapeutic compounds against ROS-mediated damage in AD.…”