Vicente-Zurdo_2022_Biomedicines_10_1510

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 beta-peptide (Abeta) aggregation, antioxidation and metal chelation. The evaluated biological properties of these hybrids included antioxidant activity; inhibition of acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and Abeta(42) aggregation; as well as promotion of cell viability and neuroprotection. All the compounds are better inhibitors of AChE than rivastigmine (IC(50) = 32.1 microM), but compounds of series 5 are better inhibitors of BChE (IC(50) = 0.9-1.7 microM) 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%) Abeta 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 Abeta(42) and oxidative stress. Therefore, RIV-BIM hybrids seem to be potential drug candidates for AD with multi-target abilities.