Novel Rivastigmine Derivatives as Promising Multi-Target Compounds for Potential Treatment of Alzheimer's Disease

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 (A beta) aggregation, antioxidation and metal chelation. The evaluated biological properties of these hybrids included antioxidant activity; inhibition of acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and A beta(42) aggregation; as well as promotion of cell viability and neuroprotection. All the compounds are better inhibitors of AChE than rivastigmine (IC50 = 32.1 mu M), but compounds of series 5 are better inhibitors of BChE (IC50 = 0.9-1.7 mu M) 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%) A beta 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 A beta(42) and oxidative stress. Therefore, RIV-BIM hybrids seem to be potential drug candidates for AD with multi-target abilities.

Automated summary

Alzheimer's disease (AD) is a serious and prevalent neurodegenerative disorder for which there is no cure. Recent research has focused on developing multi-target compounds for anti-AD drugs. In this study, seven novel RIV-BIM hybrids were developed and studied. These hybrids combine the active part of the drug rivastigmine with isomeric hydroxyphenylbenzimidazole units. The hybrids showed inhibition of cholinesterases, inhibition of amyloid beta-peptide aggregation, antioxidation, and metal chelation. They also demonstrated good capacity to promote cell viability and neuroprotection. Therefore, the RIV-BIM hybrids have the potential to be drug candidates for AD with multi-target abilities.