New cyclopentaquinoline and 3,5-dichlorobenzoic acid hybrids with neuroprotection against oxidative stress for the treatment of Alzheimer’s disease

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative brain disease. Thus, drugs including donepezil, rivastigmine, and galantamine are not entirely effective in the treatment of this multifactorial disease. The present study evaluates eight derivatives ( 3a – 3h ) as candidates with stronger anti-AD potential but with less side effects. Reactive oxygen species (ROS) assays were used to assess oxidative stress which involve in the neurodegeneration. The neuroprotective properties of 3e against oxidative stress were done in three experiments using MTT test. The anti-AD potential was determined based on their anticholinesterase inhibition ability, determined using Ellman’s method, Aβ aggregation potential according to thioflavin (Th) fluorescence assay, and their antioxidative and anti-inflammatory activities. Compound 3e exhibited moderate cholinesterase inhibition activity (AChE, IC 50 = 0.131 µM; BuChE, IC 50 = 0.116 µM; SI = 1.13), significant inhibition of Aβ(1–42) aggregation (55.7%, at 5 µM) and acceptable neuroprotective activity. Extensive analysis of in vitro and in vivo assays indicates that new cyclopentaquinoline derivatives offer promise as candidates for new anti-AD drugs.

A recent update on huprine and its hybrids as a potential multifunctional agent for the treatment of Alzheimer's disease

“…According to the cholinergic hypothesis, memory impairment in AD is due to the excessive breakdown of ACh by AChE to choline and acetate (Kumar et al, 2022). The reduced level of ACh is believed to be the main cause for disease related signs such as loss of memory and cognitive functions (Czarnecka et al, 2023). Therefore, ACh balance is an central therapeutic approach for AD, and ChE inhibitors are one important therapeutic target for AD (Alzweiri et al, 2022;Azimian et al, 2023;Davis & Eckroat, 2021;Estolano-Cobián et al, 2020;He et al, 2021;Sari & Yilmaz, 2021;Suwanhom et al, 2020).…”