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Review
. 2015;22(3):373-404.
doi: 10.2174/0929867321666141106122628.

Recent development of multifunctional agents as potential drug candidates for the treatment of Alzheimer's disease

Natalia Guzior, Anna Wieckowska, Dawid Panek, Barbara Malawska  1
Affiliations
Review

Recent development of multifunctional agents as potential drug candidates for the treatment of Alzheimer's disease

Natalia Guzior et al. Curr Med Chem. 2015.

Abstract

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 antiaggregation activity, inhibition of β-secretase and monoamine oxidase, an antioxidant and metal chelating activity, NOreleasing 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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Figures

Fig.(1)
Fig.(1)
Drugs approved for the treatment of AD.
Fig.(2)
Fig.(2)
Structures of selected multifunctional ligands, potential anti-Alzheimer's drugs.
Fig.(3)
Fig.(3)
Tacrine heterodimers as cholinesterase and Aβ aggregation inhibitors.
Fig.(4)
Fig.(4)
Donepezil-related derivatives with Aβ anti-aggregation activity.
Fig.(5)
Fig.(5)
Benzotriazinones and triazafluoranthenones with AChE/BuChE inhibitory activity and Aβ anti-aggregation activity.
Fig.(6)
Fig.(6)
Diarylimidazole derivatives - selective BuChE and Aβ aggregation inhibitors.
Fig.(7)
Fig.(7)
Isaindigotone derivative as dual cholinesterase and Aβ aggregation inhibitor.
Fig.(8)
Fig.(8)
Structure of multifunctional derivative of isoquinoline - chelerythrine - an inhibitor of hAChE, hBuChE and Aβ aggregation.
Fig.(9)
Fig.(9)
Multifunctional coumarin and chalcone derivatives with AChE/BuChE and Aβ aggregation inhibitory activity.
Fig.(10)
Fig.(10)
Tacrine-4-oxo-4H-chromene hybrids as AChE, BuChE and BACE1 inhibitors.
Fig.(11)
Fig.(11)
Huprine based hybrids - hAChE, hBuChE, BACE1 and Aβ aggregation inhibitors.
Fig.(12)
Fig.(12)
Multifunctional pyrimidine derivatives with AChE/BuChE, BACE1 and Aβ inhibitory activity.
Fig.(13)
Fig.(13)
Benzamide derivatives as AChE/BuChE, BACE1 inhibitors.
Fig.(14)
Fig.(14)
Tryptoline and tryptamine triazole derivatives - BACE1 and Aβ aggregation inhibitors with antioxidant and metal chelating properties
Fig.(15)
Fig.(15)
Benzylpiperidine derivatives as MAO inhibitors with anti-cholinesterase activity.
Fig.(16)
Fig.(16)
Tacrine derivatives with MAO and cholinesterase inhibitory activity.
Fig.(17)
Fig.(17)
Pyrazoline derivatives with MAO and AChE inhibitory activity.
Fig.(17)
Fig.(17)
Multifunctional berberine derivatives with antioxidant activity.
Fig.(19)
Fig.(19)
Tacrine derivatives with the antioxidant properties.
Fig.(20)
Fig.(20)
Tacrine hybrids - cholinesterase and Aβ aggregation inhibitors with antioxidant properties.
Fig.(21)
Fig.(21)
Donepezil-ebselen hybrid compounds - cholinesterase inhibitors with the antioxidant properties.
Fig.(22)
Fig.(22)
Carbamate derivatives of indoline with antioxidant properties and anti-cholinesterase activity.
Fig.(23)
Fig.(23)
Lipoic acid derivatives as antioxidants and cholinesterase inhibitors.
Fig.(24)
Fig.(24)
Curcumin and its dimethylaminomethyl-substituted derivatives as antioxidants
Fig.(25)
Fig.(25)
Flavonoid derivatives as cholinesterase inhibitors with Aβ anti-aggregating and metal chelating properties.
Fig.(26)
Fig.(26)
Coumarin and rhein derivatives as cholinesterase inhibitors with metal chelating properties.
Fig.(27)
Fig.(27)
Indanone derivatives as cholinesterase and monoamine oxidase inhibitors with metal chelating properties.
Fig.(28)
Fig.(28)
Rutaecarpine derivative as a multifunctional metal chelator.
Fig.(29)
Fig.(29)
Resveratrol derivatives as metal-chelating agents with additional biological properties.
Fig.(30)
Fig.(30)
Tacrine-ferulic acid-NO-donor trihybrid and its precursors.
Fig.(31)
Fig.(31)
Tacrine-flurbiprofen hybrid compound and its NO-releasing analogue.
Fig.(32)
Fig.(32)
Galantamine and its simplified analogue with NO-releasing nitrate group.
Fig.(33)
Fig.(33)
4-Phenyl-2-aminothiazole-tacrine hybrids - cholinesterase and Aβ aggregation inhibitors with Ca2+ overload blocking activity.
Fig.(34)
Fig.(34)
N-acylamiophenothiazine derivative with the neuroprotective activity.
Fig.(35)
Fig.(35)
Cystamine-tacrine dimer.
Fig.(36)
Fig.(36)
Memagal - a chimera derivative of galantamine and memantine.
Fig.(37)
Fig.(37)
Latrepirdine-based bivalent ligand with anti-cholinesterase, Aβ anti-aggregation activity and neuroprotective effect.
Fig.(38)
Fig.(38)
LY320135 - CB1 receptor antagonist and MTDLs against AD, targeting AChE, BuChE, amyloid-β formation and cannabinoid receptors.
Fig.(39)
Fig.(39)
Indole-based CB2 receptor agonist JWH-015 and indazole-based compounds CB2 receptor agonists with BuChE inhibitory activity and antioxidant properties.
Fig.(40)
Fig.(40)
Dual-acting diether derivatives of homopiperidine with histamine H3 receptor antagonistic and anticholinesterase activity.
Fig.(41)
Fig.(41)
Tri- and tetracyclic derivatives acting as dual AChE inhibitors and hH3 receptor antagonists
Fig.(42)
Fig.(42)
An isoliquiritigenin derivative with activity against 5-LO and Aβ aggregation.
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