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7-Methoxytacrine-p-Anisidine Hybrids as Novel Dual Binding Site Acetylcholinesterase Inhibitors for Alzheimer's Disease Treatment.

ABSTRACT: Alzheimer's disease (AD) is a debilitating progressive neurodegenerative disorder that ultimately leads to the patient's death. Despite the fact that novel pharmacological approaches endeavoring to block the neurodegenerative process are still emerging, none of them have reached use in clinical practice yet. Thus, palliative treatment represented by acetylcholinesterase inhibitors (AChEIs) and memantine are still the only therapeutics used. Following the multi-target directed ligands (MTDLs) strategy, herein we describe the synthesis, biological evaluation and docking studies for novel 7-methoxytacrine-p-anisidine hybrids designed to purposely target both cholinesterases and the amyloid cascade. Indeed, the novel derivatives proved to be effective non-specific cholinesterase inhibitors showing non-competitive AChE inhibition patterns. This compounds' behavior was confirmed in the subsequent molecular modeling studies.

SUBMITTER: Korabecny J

PROVIDER: S-EPMC6331912 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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7-Methoxytacrine-p-Anisidine Hybrids as Novel Dual Binding Site Acetylcholinesterase Inhibitors for Alzheimer's Disease Treatment.

Korabecny Jan J Andrs Martin M Nepovimova Eugenie E Dolezal Rafael R Babkova Katerina K Horova Anna A Malinak David D Mezeiova Eva E Gorecki Lukas L Sepsova Vendula V Hrabinova Martina M Soukup Ondrej O Jun Daniel D Kuca Kamil K

Molecules (Basel, Switzerland) 20151210 12

Alzheimer's disease (AD) is a debilitating progressive neurodegenerative disorder that ultimately leads to the patient's death. Despite the fact that novel pharmacological approaches endeavoring to block the neurodegenerative process are still emerging, none of them have reached use in clinical practice yet. Thus, palliative treatment represented by acetylcholinesterase inhibitors (AChEIs) and memantine are still the only therapeutics used. Following the multi-target directed ligands (MTDLs) str ...[more]

PMID: 26690394

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Project description:BackgroundsAlzheimer's disease (AD) is a multifactorial neurodegenerative disease. The treatment of AD through multiple pathological targets may generate therapeutic efficacy better. The multifunctional molecules that simultaneously hit several pathological targets have been of great interest in the intervention of AD.MethodsHere, we combined the chalcone scaffold with carbamate moiety and 5,6-dimethoxy-indanone moiety to generate a novel multi-target-directed ligand (MTDL) molecule (E)-3-((5,6-dimethoxy-1-oxo-1,3-dihydro-2H-inden-2-ylidene)-methyl)phenylethyl(methyl) carbamate (named AP5). In silico approaches were used to virtually predict the binding interaction of AP5 with AChE, the drug-likeness, and BBB penetrance, and later validated by evaluation of pharmacokinetics (PK) in vivo by LC-MS/MS. Moreover, studies were conducted to examine the potential of AP5 for inhibiting AChE and AChE-induced amyloid-β (Aβ) aggregation, attenuating neuroinflammation, and providing neuroprotection in the APP/PS1 model of AD.ResultsWe found that AP5 can simultaneously bind to the peripheral and catalytic sites of AChE by molecular docking. AP5 exhibited desirable pharmacokinetic (PK) characteristics including oral bioavailability (67.2%), >10% brain penetrance, and favorable drug-likeness. AP5 inhibited AChE activity and AChE-induced Aβ aggregation in vivo and in vitro. Further, AP5 lowered Aβ plaque deposition and insoluble Aβ levels in APP/PS1 mice. Moreover, AP5 exerted anti-inflammatory responses by switching microglia to a disease-associated microglia (DAM) phenotype and preventing A1 astrocytes formation. The phagocytic activity of microglial cells to Aβ was recovered upon AP5 treatment. Importantly, chronic AP5 treatment significantly prevented neuronal and synaptic damage and memory deficits in AD mice.ConclusionTogether, our work demonstrated that AP5 inhibited the AChE activity, decreased Aβ plaque deposition by interfering Aβ aggregation and promoting microglial Aβ phagocytosis, and suppressed inflammation, thereby rescuing neuronal and synaptic damage and relieving cognitive decline. Thus, AP5 can be a new promising candidate for the treatment of AD.

Dataset Information

7-Methoxytacrine-p-Anisidine Hybrids as Novel Dual Binding Site Acetylcholinesterase Inhibitors for Alzheimer's Disease Treatment.

Publications

7-Methoxytacrine-p-Anisidine Hybrids as Novel Dual Binding Site Acetylcholinesterase Inhibitors for Alzheimer's Disease Treatment.

Similar Datasets

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