Abstract
Tacrine (THA), the first clinically effective acetylcholinesterase (AChE) inhibitor and the first approved drug for the treatment of Alzheimer’s disease (AD), was withdrawn from the market due to its side effects, particularly its hepatotoxicity. Nowadays, THA serves as a valuable scaffold for the design of novel agents potentially applicable for AD treatment. One such compound, namely 7-methoxytacrine (7-MEOTA), exhibits an intriguing profile, having suppressed hepatotoxicity and concomitantly retaining AChE inhibition properties. Another interesting class of AChE inhibitors represents Huprines, designed by merging two fragments of the known AChE inhibitors—THA and (−)-huperzine A. Several members of this compound family are more potent human AChE inhibitors than the parent compounds. The most promising are so-called huprines X and Y. Here, we report the design, synthesis, biological evaluation, and in silico studies of 2-methoxyhuprine that amalgamates structural features of 7-MEOTA and huprine Y in one molecule.
Highlights
Alzheimer’s disease (AD) is neurodegenerative disorder which manifests itself in neurocognitive dysfunction
We report on the synthesis, exploiting a merging approach to yield 2-methoxyhuprine ((±)-1) (Figure 2)
We report on the biochemical studies, including cholinesterase inhibition, preliminary toxicity on HepG2 cell line, and synthesis, biochemical studies, including cholinesterase inhibition, preliminary toxicity on HepG2 cell line, in silico study in the human AChE and human BChE active sites
Summary
Alzheimer’s disease (AD) is neurodegenerative disorder which manifests itself in neurocognitive dysfunction (e.g., memory loss, behavioral abnormalities, depression, hallucinations, delusion, and agitation). The neuropathological changes associated with AD lead to consistent irreversible loss of neurons and synapses throughout the brain. This results in the aggravation of AD symptoms and in patient’s death [1]. AD is considered one of the major public health issues due to the lack of effective treatment and demographic aging, which will increase the number of people suffering from AD in the future. The economic impact of AD is another important fact to consider [2,3].
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