Centrally Active Multitarget Anti-Alzheimer Agents Derived from the Antioxidant Lead CR-6.
F Javier Pérez-ArealesMaría GarridoEster AsoManuela BartoliniAngela De SimoneAlba EspargaróTiziana GinexRaimon SabatèBelén PérezVincenza AndrisanoDolors Puigoriol-IllamolaMercé PallàsFrancisco Javier LuqueMaría Isabel LozaJosé BreaIsidro FerrerFrancisco CiruelaAngel MesseguerDiego Muñoz-TorreroPublished in: Journal of medicinal chemistry (2020)
Oxidative stress is a major pathogenic factor in Alzheimer's disease, but it should not be tackled alone rather together with other key targets to derive effective treatments. The combination of the scaffold of the polar antioxidant lead 7-methoxy-2,2-dimethylchroman-6-ol (CR-6) with that of the lipophilic cholinesterase inhibitor 6-chlorotacrine results in compounds with favorable brain permeability and multiple activities in vitro (acetylcholinesterase, butyrylcholinesterase, β-site amyloid precursor protein (APP) cleaving enzyme-1 (BACE-1), and Aβ42 and tau aggregation inhibition). In in vivo studies on wild-type and APP/presenilin 1 (PS1) mice, two selected compounds were well tolerated and led to positive trends, albeit statistically nonsignificant in some cases, on memory performance, amyloid pathology (reduced amyloid burden and potentiated non-amyloidogenic APP processing), and oxidative stress (reduced cortical oxidized proteins and increased antioxidant enzymes superoxide dismutase 2 (SOD2), catalase, glutathione peroxidase 1 (GPX1), and heme oxygenase 1 (Hmox1) and transcription factor nuclear factor-erythroid 2-related factor 2 (Nrf2)). These compounds emerge as interesting brain-permeable multitarget compounds, with a potential as anti-Alzheimer agents beyond that of the original lead CR-6.
Keyphrases
- oxidative stress
- nuclear factor
- wild type
- cognitive decline
- diabetic rats
- transcription factor
- dna damage
- ischemia reperfusion injury
- induced apoptosis
- toll like receptor
- anti inflammatory
- hydrogen peroxide
- white matter
- skeletal muscle
- protein protein
- small molecule
- adipose tissue
- nitric oxide
- amyotrophic lateral sclerosis
- ionic liquid
- immune response
- low density lipoprotein
- signaling pathway
- insulin resistance
- binding protein
- high fat diet induced
- heat stress