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Marine Natural Products, Multitarget Therapy and Repurposed Agents in Alzheimer's Disease.

ABSTRACT: Alzheimer's disease (AD) is a multifactorial disease characterized by the presence of amyloid plaques, neurofibrillary tangles, and nerve cell death that affects, mainly, older people. After decades of investigation, the search for an efficacious treatment for AD remains and several strategies can be and are being employed in this journey. In this review, four of the most promising strategies, alongside with its most promising agents under investigation or development are highlighted. Marine natural products (MNP) are a source of unique chemical structures with useful biological activities for AD treatment. One of the most promising compounds, a marine-derived acidic oligosaccharide (GV-971) just passed phase III clinical trials with a unique mechanism of action. Combination therapy and multitargeted-directed ligand therapy (MTDL) are also two important strategies, with several examples in clinical trials, based on the belief that the best approach for AD is a therapy capable of modulating multiple target pathways. Drug repurposing, a strategy that requires a smaller investment and is less time consuming, is emerging as a strong contender with a variety of pharmacological agents resurfacing in an attempt to identify a therapeutic candidate capable of modifying the course of this disease.

SUBMITTER: Martins M

PROVIDER: S-EPMC7558913 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Marine Natural Products, Multitarget Therapy and Repurposed Agents in Alzheimer's Disease.

Martins Márcia M Silva Renata R M M Pinto Madalena M Sousa Emília E

Pharmaceuticals (Basel, Switzerland) 20200911 9

Alzheimer's disease (AD) is a multifactorial disease characterized by the presence of amyloid plaques, neurofibrillary tangles, and nerve cell death that affects, mainly, older people. After decades of investigation, the search for an efficacious treatment for AD remains and several strategies can be and are being employed in this journey. In this review, four of the most promising strategies, alongside with its most promising agents under investigation or development are highlighted. Marine nat ...[more]

PMID: 32933034

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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.

Dataset Information

Marine Natural Products, Multitarget Therapy and Repurposed Agents in Alzheimer's Disease.

Publications

Marine Natural Products, Multitarget Therapy and Repurposed Agents in Alzheimer's Disease.

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