β-Carboline as a Privileged Scaffold for Multitarget Strategies in Alzheimer’s Disease Therapy

Abstract

The natural β-carboline alkaloids display similarities with neurotransmitters that can be favorably exploited to design bioactive and bioavailable drugs for Alzheimer's disease (AD) therapy. Several AD targets are currently and intensively being investigated, divided in different hypotheses: mainly the cholinergic, the amyloid β (Aβ), and the Tau hypotheses. To date, only symptomatic treatments are available involving acetylcholinesterase and NMDA inhibitors. On the basis of plethoric single-target structure−activity relationship studies, the β-carboline scaffold was identified as a powerful tool for fostering activity and molecular interactions with a wide range of AD-related targets. This knowledge can undoubtedly be used to design multitarget-directed ligands, a highly relevant strategy preferred in the context of multifactorial pathology with intricate etiology such as AD. In this review, we first individually discuss the AD targets of the β-carbolines, and then we focus on the multitarget strategies dedicated to the deliberate design of new efficient scaffolds.

Hybrid Quinoline-Thiosemicarbazone Therapeutics as a New Treatment Opportunity for Alzheimer’s Disease‒Synthesis, In Vitro Cholinesterase Inhibitory Potential and Computational Modeling Analysis

“…These include cholinergic hypothesis (pathological changes and the dysfunction of the neuro-cholinergic system), amyloid hypothesis (β-amyloid tangles and aggregations inducing neural apoptosis, tau protein hyperphosphorylation forming senile plaque), oxidative stress hypothesis (neuro-inflammation and increasing level of reactive oxygen radicals), and bio-metal hypothesis (deregulation of transition bio-metals in AD patients). Among these, the design and development of new and potent inhibitors based on central cholinergic hypothesis remains the most common and clinically tested strategy for AD therapy [4][5][6][7][8].…”

Unveiling the Multitarget Anti-Alzheimer Drug Discovery Landscape: A Bibliometric Analysis

“… A second, quite general notion is that most multitarget anti-AD compounds are designed to hit AChE and another target of interest [ 28 ]. Indeed, a large number of multitarget compounds feature pharmacophoric moieties of the approved AChE inhibitors [ 29 , 30 , 31 , 32 ], even though publications on multitarget anti-AD agents based on other pharmacophores, especially naturally occurring scaffolds such as β-carbolines [ 33 ], naphthoquinones and anthraquinones [ 34 ], or chalcones [ 35 ], just to name a few of those recently reviewed, are continuously appearing. Apart from AChE, other targets and pathogenic mechanisms that, intuitively, seem to have been commonly addressed when designing multitarget anti-AD compounds are glutamante NMDA receptors [ 36 , 37 ], β-amyloid and tau aggregation [ 38 , 39 ], glycogen synthase kinase 3β (GSK-3β) [ 40 ], biometal dyshomeostasis [ 41 ], monoamine oxidases (MAOs) [ 42 ], or oxidative stress [ 43 ].…”

Determination of Anti-Alzheimer’s Disease Activity of Selected Plant Ingredients

“…The neuropharmacology effects, including, among others, acetylcholinesterase antioxidant, anti-inflammatory inhibition and β-amyloid reduction properties, of Nigella sativa and its main component, thymoquinone, were reviewed [ 9 ]. Natural β-carboline alkaloids as a privileged scaffold for multitarget strategies in Alzheimer’s disease therapy were also reviewed [ 10 ]. Acetylcholinesterase activity inhibition, butyrylcholinesterase activity inhibition, β-amyloid aggregation inhibition, monoamine oxidases inhibition, 5-hydroxytryptamine receptor binding and other activity of the natural β-carboline derivatives were described [ 10 ].…”

“…Natural β-carboline alkaloids as a privileged scaffold for multitarget strategies in Alzheimer’s disease therapy were also reviewed [ 10 ]. Acetylcholinesterase activity inhibition, butyrylcholinesterase activity inhibition, β-amyloid aggregation inhibition, monoamine oxidases inhibition, 5-hydroxytryptamine receptor binding and other activity of the natural β-carboline derivatives were described [ 10 ].…”