Alzheimer’s disease (AD) is the most serious and prevalent neurodegenerative disorder still without cure. Since its aetiology is diverse, recent research on anti-AD drugs has been focused on multi-target compounds. In this work, seven novel hybrids (RIV–BIM) conjugating the active moiety of the drug rivastigmine (RIV) with 2 isomeric hydroxyphenylbenzimidazole (BIM) units were developed and studied. While RIV assures the inhibition of cholinesterases, BIM provides further appropriate properties, such as inhibition of amyloid β-peptide (Aβ) aggregation, antioxidation and metal chelation. The evaluated biological properties of these hybrids included antioxidant activity; inhibition of acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and Aβ42 aggregation; as well as promotion of cell viability and neuroprotection. All the compounds are better inhibitors of AChE than rivastigmine (IC50 = 32.1 µM), but compounds of series 5 are better inhibitors of BChE (IC50 = 0.9−1.7 µM) than those of series 4. Series 5 also showed good capacity to inhibit self- (42.1−58.7%) and Cu(II)-induced (40.3−60.8%) Aβ aggregation and also to narrow (22.4−42.6%) amyloid fibrils, the relevant compounds being 5b and 5d. Some of these compounds can also prevent the toxicity induced in SH-SY5Y cells by Aβ42 and oxidative stress. Therefore, RIV–BIM hybrids seem to be potential drug candidates for AD with multi-target abilities.
Neurodegenerative
diseases have been associated with brain metal
accumulation, which produces oxidative stress (OS), matrix metalloproteinases
(MMPs) induction, and neuronal cell death. Several metals have been
reported to downregulate both the nuclear factor erythroid 2-related
factor 2 (Nrf2) pathway and the antioxidant enzymes regulated by it,
mediating OS induction and neurodegeneration. Among a recently discovered
family of multitarget 7-amino-phenanthridin-6-one derivatives (
APH
) the most promising compounds were tested against metal-induced
cell death and OS in SN56 cells. These compounds, designed to have
chelating activity, are known to inhibit some MMPs and to present
antioxidant and neuroprotective effects against hydrogen peroxide
treatment to SN56 neuronal cells. However, the mechanisms that mediate
this protective effect are not fully understood. The obtained results
show that compounds
APH1
,
APH2
,
APH3
,
APH4
, and
APH5
were only able to chelate
iron and copper ions among all metals studied and that
APH3
,
APH4
, and
APH5
were also able to chelate
mercury ion. However, none of them was able to chelate zinc, cadmium,
and aluminum, thus exhibiting selective chelating activity that can
be partly responsible for their neuroprotective action. Otherwise,
our results indicate that their antioxidant effect is mediated through
induction of the Nrf2 pathway that leads to overexpression of antioxidant
enzymes. Finally, these compounds exhibited neuroprotective effects,
reversing partially or completely the cytotoxic effects induced by
the metals studied depending on the compound used.
APH4
was the most effective and safe compound.
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