Multitargeted Drugs for Treatment of Alzheimer's Disease

Cavalli, Andrea; Bolognesi, María Laura

doi:10.1002/9781118098141.ch22

Cited by 6 publications

(2 citation statements)

References 80 publications

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“…Apart from schizophrenia, cancer, and infections, polypharmacological treatments may benefit a range of other diseases, such as depression, − other psychiatric disorders, ,, neurodegeneration, − epilepsy, cardiovascular disorders, ,, arrhythmia − airway diseases, autoimmune disorders, inflammation, and pain . The Food and Drug Administration (FDA) approved numerous polypharmacological drugs in recent years, for example, asenapine, sunitinib, and dronedarone (Chart ).…”

Section: Is There a Case For Polypharmacological Drug Discovery?mentioning

confidence: 99%

Polypharmacology – Foe or Friend?

2013

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Polypharmacology describes the activity of compounds at multiple targets. Current research focuses on two aspects of polypharmacology: (1) unintended polypharmacology can lead to adverse effects; (2) polypharmacology across several disease-relevant targets can improve therapeutic efficacy, prevent drug resistance, or reduce therapeutic-target-related adverse effects. This perspective reviews these interconnected aspects of polypharmacology. The first part discusses the relevance of polypharmacology for the safety of drugs, the mitigation of safety risks, and methods to identify polypharmacological compounds early in the drug discovery process. The second part discusses the advantages of polypharmacology in the treatment of multigenic diseases and infections, and opportunities for drug discovery and drug repurposing. This perspective aims to provide a balanced view on polypharmacology, which can compromise the safety of drugs, but can also confer superior efficacy.

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Section: Is There a Case For Polypharmacological Drug Discovery?mentioning

confidence: 99%

Polypharmacology – Foe or Friend?

2013

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“…On the other hand, it has been observed that selective ligands with high specificity for a single target, often lacked clinical efficacy. MTDL approach may be achieved either by connecting different molecules endowed with high potency for different targets or a single agent able to modulate multiple targets simultaneously [ 25 - 29 ]. Complexity of AD and a lack of effective treatment of the disease prompted many research teams to search for multiple ligands.…”

Section: Introductionmentioning

confidence: 99%

Recent Development of Multifunctional Agents as Potential Drug Candidates for the Treatment of Alzheimer’s Disease

Guzior¹,

Więckowska²,

Panek³

et al. 2014

CMC

284

176

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Alzheimer’s disease (AD) is a complex and progressive neurodegenerative disorder. The available therapy is limited to the symptomatic treatment and its efficacy remains unsatisfactory. In view of the prevalence and expected increase in the incidence of AD, the development of an effective therapy is crucial for public health. Due to the multifactorial aetiology of this disease, the multi-target-directed ligand (MTDL) approach is a promising method in search for new drugs for AD. This review updates information on the development of multifunctional potential anti-AD agents published within the last three years. The majority of the recently reported structures are acetylcholinesterase inhibitors, often endowed with some additional properties. These properties enrich the pharmacological profile of the compounds giving hope for not only symptomatic but also causal treatment of the disease. Among these advantageous properties, the most often reported are an amyloid-β anti-aggregation activity, inhibition of β-secretase and monoamine oxidase, an antioxidant and metal chelating activity, NO-releasing ability and interaction with cannabinoid, NMDA or histamine H3 receptors. The majority of novel molecules possess heterodimeric structures, able to interact with multiple targets by combining different pharmacophores, original or derived from natural products or existing therapeutics (tacrine, donepezil, galantamine, memantine). Among the described compounds, several seem to be promising drug candidates, while others may serve as a valuable inspiration in the search for new effective therapies for AD.

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New tacrine–acridine hybrids as promising multifunctional drugs for potential treatment of Alzheimer's disease

Chufarova

Czarnecka

Skibiński

et al. 2018

Archiv der Pharmazie

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The synthesis, biological tests, and computer modeling of a series of novel promising tacrine hybrids for the therapy of Alzheimer's disease are reported. Firstly, new tacrine-acridine hybrids with different carbon linker lengths were synthesized. Secondly, all the compounds were tested in vitro for their ability to inhibit acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) enzyme activity. After that, the most promising compound 3d was tested using the amyloid-β aggregation assay. To evaluate possible toxic effects, cytotoxicity tests were conducted. The most active compound 3d (IC = 7.6 pM for AChE and 1.7 pM for BuChE) appeared to be a much more active inhibitor than tacrine (IC = 89.9 nM for AChE and 14.9 nM for BuChE). At the highest concentration (100 μM), 3d exhibited 57.77% activity, retaining it as the concentration decreased: 50 μM - 54.74%, 20 μM - 48.28%, 10 μM - 31.66%. The compound showed no significant cytotoxic effect at the tested concentrations. At the end, docking studies using methods of computer modeling were performed to visualize the binding mode of the inhibitor 3d. It showed dual-binding mode for AChE, by binding to the catalytic anionic site and the peripheral anionic site simultaneously. Thus, compound 3d is a promising multitarget hybrid that can be used for the treatment of Alzheimer's disease.

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Multitargeted Drugs for Treatment of Alzheimer's Disease

Cited by 6 publications

References 80 publications

Polypharmacology – Foe or Friend?

Polypharmacology – Foe or Friend?

Recent Development of Multifunctional Agents as Potential Drug Candidates for the Treatment of Alzheimer’s Disease

New tacrine–acridine hybrids as promising multifunctional drugs for potential treatment of Alzheimer's disease

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