Journal
METALLOMICS
Volume 10, Issue 10, Pages 1460-1475Publisher
ROYAL SOC CHEMISTRY
DOI: 10.1039/c8mt00143j
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Funding
- Portuguese Foundation of Science and Technology (FCT) [UID/QUO/00100/2013]
- Erasmus Namaste program [NAMASTE_20130125]
- Erasmus Experts sustain program [EXPERTS_20127536]
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Alzheimer's disease (AD) is a severe age-dependent neurodegenerative disorder affecting several million people worldwide. So far, there is no adequate medication to prevent or slow down the progression of the disease, only medication with palliative effects allowing temporary symptomatic reliefs. As part of our continuing efforts into the development of innovative drugs following a polypharmacological strategy, we decided to use a former anti-AD palliative drug (tacrine) and to reposition it by hybridization with a metal chelating drug (deferiprone, DFP). This combination endows the hybrids with good capacity to inhibit acetylcholinesterase (low micromolar range) and self-/Cu-induced A aggregation (up to ca. 90%) as well as a good radical scavenging ability (micromolar range) and metal (M) chelating capacity, with pM (pM = -log[M], C-L/C-M = 10, C-M = 10(-6) M at pH = 7.4, M = Fe, Cu, Zn) values close to those of DFP. The most promising compounds have 2-hydroxypropyl linkers, and a selection of compounds have demonstrated neuroprotective roles in neuroblastoma cells treated with A(1-42) and ascorbate/iron stressors. Consequently, these hybrids can be considered as attractive multipotent therapeutic molecules that will eventually play key roles against AD progression, namely in the control of cholinergic dysfunction, amyloid peptide aggregation, oxidative stress, and metal modulation, besides presenting a good pharmacokinetic profile.
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