Abstract
Tacrine was the first drug to be approved for Alzheimer’s disease (AD) treatment, acting as a cholinesterase inhibitor. The neuropathological hallmarks of AD are amyloid-rich senile plaques, neurofibrillary tangles, and neuronal degeneration. The portfolio of currently approved drugs for AD includes acetylcholinesterase inhibitors (AChEIs) and N-methyl-d-aspartate (NMDA) receptor antagonist. Squaric acid is a versatile structural scaffold capable to be easily transformed into amide-bearing compounds that feature both hydrogen bond donor and acceptor groups with the possibility to create multiple interactions with complementary sites. Considering the relatively simple synthesis approach and other interesting properties (rigidity, aromatic character, H-bond formation) of squaramide motif, we combined this scaffold with different tacrine-based derivatives. In this study, we developed 21 novel dimers amalgamating squaric acid with either tacrine, 6-chlorotacrine or 7-methoxytacrine representing various AChEIs. All new derivatives were evaluated for their anti-cholinesterase activities, cytotoxicity using HepG2 cell line and screened to predict their ability to cross the blood-brain barrier. In this contribution, we also report in silico studies of the most potent AChE and BChE inhibitors in the active site of these enzymes.
Highlights
Alzheimer’s disease (AD), the most common form of dementia [1], is symptomatically treated with inhibitors of acetylcholinesterase (AChE, 3.1.1.7)
Intermediates of general structure 1 varying in the length of alkyl chains were prepared according to previously published methods [45,46]
We observed the formation of monomeric analogues of squaramides, but these were chemically unstable when isolated and were excluded from further biological studies
Summary
Alzheimer’s disease (AD), the most common form of dementia [1], is symptomatically treated with inhibitors of acetylcholinesterase (AChE, 3.1.1.7). This type of serine protease catalyzes the hydrolysis of the neurotransmitter acetylcholine (ACh) to choline and acetic acid [2]. Three AChE inhibitors (AChEIs), namely, donepezil, galantamine, and rivastigmine, are the representatives of so-called “cholinergic hypothesis” used currently as the main drugs for AD treatment [5]. AD has been recognized by deposition of two types of proteins, extracellularly accumulated β-amyloid (Aβ) protein due to abnormal processing of amyloid precursor protein (APP), and intracellular neurofibrillary tangles composed from hyperphosphorylated tau protein [6].
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