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N-alkyl carbazole derivatives as new tools for Alzheimer's disease: preliminary studies.

ABSTRACT: Alzheimer's disease (AD) is a progressive and age-related neurodegenerative disorder affecting brain cells and is the most common form of "dementia", because of the cognitive detriment which takes place. Neuronal disruption represents its major feature, due to the cytosolic accumulation of amyloid ?-peptide (A?) which leads to senile plaques formation and intracellular neurofibrillary tangles. Many studies have focused on the design and therapeutic use of new molecules able to inhibit A? aggregation. In this context, we evaluated the ability of two recently synthesized series of N-alkyl carbazole derivatives to increase the A? soluble forms, through molecular docking simulations and in vitro experiments. Our data evidenced that two carbazole derivatives, the most active, adopt distinct binding modes involving key residues for A? fibrillization. They exhibit a good interfering activity on A? aggregation in mouse (N2a) cells, stably expressing wild-type human amyloid precursor protein (APP) 695. These preliminary results are promising and we are confident that the N-alkyl carbazole derivatives may encourage next future studies needed for enlarging the knowledge about the AD disease approach.

SUBMITTER: Saturnino C

PROVIDER: S-EPMC6271900 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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N-alkyl carbazole derivatives as new tools for Alzheimer's disease: preliminary studies.

Saturnino Carmela C Iacopetta Domenico D Sinicropi Maria Stefania MS Rosano Camillo C Caruso Anna A Caporale Angelamaria A Marra Nancy N Marengo Barbara B Pronzato Maria Adelaide MA Parisi Ortensia Ilaria OI Longo Pasquale P Ricciarelli Roberta R

Molecules (Basel, Switzerland) 20140702 7

Alzheimer's disease (AD) is a progressive and age-related neurodegenerative disorder affecting brain cells and is the most common form of "dementia", because of the cognitive detriment which takes place. Neuronal disruption represents its major feature, due to the cytosolic accumulation of amyloid β-peptide (Aβ) which leads to senile plaques formation and intracellular neurofibrillary tangles. Many studies have focused on the design and therapeutic use of new molecules able to inhibit Aβ aggrega ...[more]

PMID: 24991761

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Project description:A series of previously synthesized conjugates of tacrine and salicylamide was extended by varying the structure of the salicylamide fragment and using salicylic aldehyde to synthesize salicylimine derivatives. The hybrids exhibited broad-spectrum biological activity. All new conjugates were potent inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) with selectivity toward BChE. The structure of the salicylamide moiety exerted little effect on anticholinesterase activity, but AChE inhibition increased with spacer elongation. The most active conjugates were salicylimine derivatives: IC50 values of the lead compound 10c were 0.0826 µM (AChE) and 0.0156 µM (BChE), with weak inhibition of the off-target carboxylesterase. The hybrids were mixed-type reversible inhibitors of both cholinesterases and displayed dual binding to the catalytic and peripheral anionic sites of AChE in molecular docking, which, along with experimental results on propidium iodide displacement, suggested their potential to block AChE-induced β-amyloid aggregation. All conjugates inhibited Aβ42 self-aggregation in the thioflavin test, and inhibition increased with spacer elongation. Salicylimine 10c and salicylamide 5c with (CH2)8 spacers were the lead compounds for inhibiting Aβ42 self-aggregation, which was corroborated by molecular docking to Aβ42. ABTS•+-scavenging activity was highest for salicylamides 5a-c, intermediate for salicylimines 10a-c, low for F-containing salicylamides 7, and non-existent for methoxybenzoylamides 6 and difluoromethoxybenzoylamides 8. In the FRAP antioxidant (AO) assay, the test compounds displayed little or no activity. Quantum chemical analysis and molecular dynamics (MD) simulations with QM/MM potentials explained the AO structure-activity relationships. All conjugates were effective chelators of Cu2+, Fe2+, and Zn2+, with molar compound/metal (Cu2+) ratios of 2:1 (5b) and ~1:1 (10b). Conjugates exerted comparable or lower cytotoxicity than tacrine on mouse hepatocytes and had favorable predicted intestinal absorption and blood-brain barrier permeability. The overall results indicate that the synthesized conjugates are promising new multifunctional agents for the potential treatment of AD.

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N-alkyl carbazole derivatives as new tools for Alzheimer's disease: preliminary studies.

Publications

N-alkyl carbazole derivatives as new tools for Alzheimer's disease: preliminary studies.

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