Abstract
A structural series of 7-MEOTA-adamantylamine thioureas was designed, synthesized and evaluated as inhibitors of human acetylcholinesterase (hAChE) and human butyrylcholinesterase (hBChE). The compounds were prepared based on the multi-target-directed ligand strategy with different linker lengths (n = 2–8) joining the well-known NMDA antagonist adamantine and the hAChE inhibitor 7-methoxytacrine (7-MEOTA). Based on in silico studies, these inhibitors proved dual binding site character capable of simultaneous interaction with the peripheral anionic site (PAS) of hAChE and the catalytic active site (CAS). Clearly, these structural derivatives exhibited very good inhibitory activity towards hBChE resulting in more selective inhibitors of this enzyme. The most potent cholinesterase inhibitor was found to be thiourea analogue 14 (with an IC50 value of 0.47 µM for hAChE and an IC50 value of 0.11 µM for hBChE, respectively). Molecule 14 is a suitable novel lead compound for further evaluation proving that the strategy of dual binding site inhibitors might be a promising direction for development of novel AD drugs.
Highlights
Alzheimer’s disease (AD) is the most common form of dementia
The general synthetic procedure for 7-MEOTA-adamantylamine heterodimers is shown in Scheme 1
Spectral data were in good agreement with the literature characterization [28]
Summary
Alzheimer’s disease (AD) is the most common form of dementia It is the fourth leading cause of mortality in the US alone [1]. Of all cases, lasting for about 3–20 years from diagnosis to death It was first documented in 1906 when Alois Alzheimer, a German psychiatrist and neuropathologist, reported the curious case of one of his patients, who suffered from memory problems, speaking impairment and difficulty with comprehensive understanding [2]. AD is a neurodegenerative disorder that results in the progressive and irreversible cognitive impairment, memory loss, and decline in language [3–5]. Several diverse hallmarks, such as deposits of aberrant proteins (β-amyloid and τ-protein), oxidative stress, dyshomeostasis of biometals, and low levels of acetylcholine (ACh) appear to play significant roles in the pathophysiology of the disease [6,7]. AD represents an economic burden, which causes profound social problems to both society and families [8,9]
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