Amyloid Beta Hypothesis: Attention to β- and γ-Secretase Modulators

The amyloid cascade hypothesis poses one possible explanation for the onset and progression of Alzheimer’s disease (AD). With this respect, neurotoxic effect is attributed to soluble and diffusive amyloid-β (Aβ) oligomers. Aβ peptides are produced by proteolytic cleavage of the hydrophobic transmembrane portion of the amyloid precursor protein (APP) by successive action of β- and γ-secretases. Aβ peptides are generated in several isoforms, out of which the most pronounced are Aβ40 and Aβ42 being the major constituents of amyloid plaques found in AD patients’ brains. Since the indisputable evidence pointed out to Aβ oligomers as toxic agents, several pathways to modulate or control the aggregation have been inspected. Given all these aspects, inhibitors of the β- and γ-secretases have gained the most attention. This chapter presents amyloid cascade hypothesis with current progress in the development of β- and γ-secretase modulators to counteract the Aβ burden

7-Methoxytacrine-Adamantylamine Heterodimers as Cholinesterase Inhibitors in Alzheimer’s Disease Treatment — Synthesis, Biological Evaluation and Molecular Modeling Studies

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Profiling donepezil template into multipotent hybrids with antioxidant properties

Alzheimer’s disease is debilitating neurodegenerative disorder in the elderly. Current therapy relies on administration of acetylcholinesterase inhibitors (AChEIs) -donepezil, rivastigmine, galantamine, and N-methyl-d-aspartate receptor antagonist memantine. However, their therapeutic effect is only short-term and stabilizes cognitive functions for up to 2 years. Given this drawback together with other pathological hallmarks of the disease taken into consideration, novel approaches have recently emerged to better cope with AD onset or its progression. One such strategy implies broadening the biological profile of AChEIs into so-called multi-target directed ligands (MTDLs). In this review article, we made comprehensive literature survey emphasising on donepezil template which was structurally converted into plethora of MTLDs preserving anti-cholinesterase effect and, at the same time, escalating the anti-oxidant potential, which was reported as a crucial role in the pathogenesis of the Alzheimer’s disease

Synthesis and Biological Evaluation of Novel Tacrine Derivatives and Tacrine–Coumarin Hybrids as Cholinesterase Inhibitors

A series of novel tacrine derivatives and tacrine–coumarin heterodimers were designed, synthesized, and biologically evaluated for their potential inhibitory effect on both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Of these compounds, tacrine–coumarin heterodimer <b>7c</b> and tacrine derivative <b>6b</b> were found to be the most potent inhibitors of human AChE (<i>h</i>AChE), demonstrating IC₅₀ values of 0.0154 and 0.0263 μM. Ligands <b>6b</b>, <b>6c</b>, and <b>7c</b> exhibited the highest levels of inhibitory activity against human BuChE (<i>h</i>BuChE), demonstrating IC₅₀ values that range from 0.228 to 0.328 μM. Docking studies were performed in order to predict the binding modes of compounds <b>6b</b> and <b>7c</b> with <i>h</i>AChE/<i>h</i>BuChE

Novel Tacrine-Scutellarin Hybrids as Multipotent Anti-Alzheimer’s Agents: Design, Synthesis and Biological Evaluation

A novel series of 6-chlorotacrine-scutellarin hybrids was designed, synthesized and the biological activity as potential anti-Alzheimer’s agents was assessed. Their inhibitory activity towards human acetylcholinesterase (hAChE) and human butyrylcholinesterase (hBChE), antioxidant activity, ability to cross the blood-brain barrier (BBB) and hepatotoxic profile were evaluated in vitro. Among these compounds, hybrid K1383, bearing two methylene tether between two basic scaffolds, was found to be very potent hAChE inhibitor (IC50 = 1.63 nM). Unfortunately, none of the hybrids displayed any antioxidant activity (EC50 ≥ 500 μM). Preliminary data also suggests a comparable hepatotoxic profile with 6-Cl-THA (established on a HepG2 cell line). Kinetic studies performed on hAChE with the most active compound in the study, K1383, pointed out to a mixed, non-competitive enzyme inhibition. These findings were further corroborated by docking studies

Development of 2-Methoxyhuprine as Novel Lead for Alzheimer’s Disease Therapy

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