New Multitarget Rivastigmine-Indole Hybrids as Potential Drug Candidates for Alzheimer's Disease

Area of Science:

• Medicinal Chemistry
• Neuroscience
• Drug Discovery

Background:

• Alzheimer's disease (AD) is a complex, multifactorial neurodegenerative disorder with no existing cure.
• Current treatments are limited, necessitating the development of novel multitarget therapeutic strategies.
• Neuropathological hallmarks of AD provide targets for new drug development.

Purpose of the Study:

• To design, synthesize, and evaluate novel rivastigmine-indole (RIV-IND) hybrids as potential multitarget agents against Alzheimer's disease.
• To investigate the compounds' inhibitory effects on acetylcholinesterase (AChE) and butyrylcholinesterase (BChE).
• To assess their antioxidant activity, inhibition of amyloid-beta (Aβ) aggregation, and neuroprotective potential.

Main Methods:

• Synthesis of nine RIV-IND hybrid compounds.
• Molecular docking studies to predict binding interactions with AChE and BChE.
• In vitro assays for enzyme inhibition (AChE, BChE), radical scavenging activity, and Aβ₄₂ self-aggregation inhibition.
• Cell-based assays to evaluate protection against Aβ_1-42-induced toxicity.
• In silico evaluation of drug-likeness and oral availability.

Main Results:

• Compounds 5a3 and 5c3 exhibited potent AChE inhibition, surpassing the parent rivastigmine drug.
• All hybrids with a hydroxyl substituent on the indole moiety displayed significant antioxidant activity.
• Compounds 5a3, 5b3, and 5c3 effectively inhibited Aβ₄₂ self-aggregation.
• Compounds 5b2 and 5c2 demonstrated neuroprotective effects against Aβ_1-42-induced cellular toxicity.
• In silico analysis indicated favorable drug-likeness and potential oral bioavailability for all hybrids.

Conclusions:

• The synthesized RIV-IND hybrids show potential as multitarget therapeutic agents for Alzheimer's disease.
• Compounds 5a3 and 5c3 emerged as promising lead compounds for further preclinical investigation.
• The multitarget approach combining enzyme inhibition and anti-amyloid activity is a viable strategy for AD drug development.