Bifunctional phenolic-choline conjugates as anti-oxidants and acetylcholinesterase inhibitors

  title={Bifunctional phenolic-choline conjugates as anti-oxidants and acetylcholinesterase inhibitors},
  author={Jaroslav {\vS}ebest{\'i}k and S{\'e}rgio M. Marques and Pedro Lu{\'i}s Vieira Fal{\'e} and Susana Santos and Daniela Moniz Ardu{\'i}no and Sandra Morais Cardoso and Catarina R. Oliveira and M. Luisa Serralheiro and M. Am{\'e}lia Santos},
  journal={Journal of Enzyme Inhibition and Medicinal Chemistry},
  pages={485 - 497}
Because of the complex cascade of molecular events that can occur in the brain of an Alzheimer’s disease (AD) patient, the therapy of this neurodegenerative disease seems more likely to be achieved by multifunctional drugs. Herein, a new series of dual-targeting ligands have been developed and in vitro bioevaluated. Their architecture is based on conjugating the acetylcholinesterase inhibition and anti-oxidant properties in one molecular entity. Specifically, a series of naturally occurring… 

Multifunctional iron-chelators with protective roles against neurodegenerative diseases.

The design and synthesis of the new hybrid compounds are described, followed by the assessment of solution properties, namely iron chelation and anti-oxidant capacity, and their effects on the viability of neuronal cells stressed with Aβ(42).

New Tacrine Hybrids with Natural‐Based Cysteine Derivatives as Multitargeted Drugs for Potential Treatment of Alzheimer's Disease

A set of natural‐based hybrid compounds by conjugation of a tacrine moiety with an S‐allylcysteine (garlic constituent) or S‐propargylcy Steine moiety aimed at improving the cholinergic system and neuroprotective capacity are explored.

Multi‐Targeting Tacrine Conjugates with Cholinesterase and Amyloid‐Beta Inhibitory Activities: New Anti‐Alzheimer's Agents

Two novel series of TAC‐fenbufen/menbutone conjugated molecules were developed to hit the multifactorial disease targets and may be potential drug lead molecules in the treatment of AD.

Acetamide Derivatives of Chromen‐2‐ones as Potent Cholinesterase Inhibitors

The above‐selected compounds were found to be effective inhibitors of AChE‐induced and self‐mediated Aβ1–42 aggregation, and provide insights for further optimization of the scaffolds for designing the next generation of compounds as lead cholinesterase inhibitors.

Donepezil structure-based hybrids as potential multifunctional anti-Alzheimer’s drug candidates

The hybrids containing chelating groups showed improvement in the inhibition of Cu-induced Aβ42 aggregation and the antioxidant capacity, and neuroprotective effects of these compounds were evidenced in neuroblastoma cells after Aβ1–42 induced toxicity.

New hydroxypyridinone iron-chelators as potential anti-neurodegenerative drugs.

A, B and C were more effective than DFP (a 3,4-HP iron-chelating agent in clinical use) in MPP+ induced cell death and evidenced a neuroprotective and antiapoptotic role for the compounds studied.

Design, synthesis, and biological evaluation of conformationally restricted rivastigmine analogues.

A series of conformationally restricted analogues of 1 are designed by including the dimethylamino-alpha-methylbenzyl moiety in different tricyclic systems, supported by a superimposition between the conformation of 1 and the carbon derivative 4, as obtained from Monte Carlo simulations, and validated the idea that the tricyClic derivatives might act as rigid analogue of 1.

Progress in acetylcholinesterase inhibitors for Alzheimer's disease: an update

A review of patents filed during 2005 – 2007 dealing with new AChEIs and their potential application for AD treatment points out new chemical structures and scaffolds for designing new AD therapeutic agents as well as new combinations or MTDLs.

Drugs that target cholinesterases

Clinical results on the effect of these drugs on cognition and more recently on behavioral symptoms in AD confirmed predictions of potential clinical efficacy based on laboratory data.

Treatment of Alzheimer’s Disease with a Cholinesterase Inhibitor Combined with Antioxidants

A formula (formula F) was prepared to counteract oxidative stress (OS) in the brain and significant decreases in OS and HCy were only observed when there was an increase in glutathione and a decrease in sickle erythrocytes in patients treated with formula F.

Site-activated multifunctional chelator with acetylcholinesterase and neuroprotective-neurorestorative moieties for Alzheimer's therapy.

A novel prochelator HLA20A with improved cytotoxicity shows little affinity for metal ions until it is activated by binding and inhibiting acetylcholinesterase, releasing an active chelator Hla20 that modulates amyloid precursor protein regulation and beta-amyloid reduction.

Multi-target-directed drug design strategy: from a dual binding site acetylcholinesterase inhibitor to a trifunctional compound against Alzheimer's disease.

A design strategy to convert a dual-binding site AChE inhibitor into triple functional compounds with promising in vitro profile against multifactorial syndromes, such as Alzheimer's disease, is

Rational approach to discover multipotent anti-Alzheimer drugs.

Lipocrine is the first compound that inhibits the catalytic activity of A ChE and AChE-induced amyloid-beta aggregation and protects against reactive oxygen species and emerged as a valuable pharmacological tool to investigate Alzheimer's disease and as a promising lead compound for new anti-Alzheimer drugs.