Natural Chimeras of Existing Drugs for Alzheimer’s Disease: Expanding the Target Landscape

Abstract

Alzheimer’s disease (AD) has emerged as a complex, multi-faceted, neurodegenerative disorder. Multiple mechanisms seem to play a part in its pathogenesis, including amyloid beta aggregation, cholinergic deficit, oxidative stress and neuroinflammation. The current FDA-approved anticholinesterase drugs addressing a single mechanism have turned out to be palliative rather than curative. A number of natural medicinal bioactive are known, which have the potential to overcome many of the unaddressed causal mechanisms contributing to AD. They act as excellent antioxidants, metal chelators, anti-inflammatory mediators and are neuroprotectives. Natural products also have the inherent capability of overcoming some of the adverse effects caused by the currently available drugs. Several researchers have worked on the development of chimeric compounds for AD, in which known cholinesterase inhibitors are linked with natural bioactive components. The resulting novel molecular entities formed have been shown to simultaneously modulate multiple targets with higher efficacy and better safety profiles, demonstrated in experimental models. This review presents a compilation and rational analysis of several natural chimeras of known anti-AD drugs, explored to expand the efficacy and safety profile of current FDA-approved anti-Alzheimer’s medications.

Keywords: Alzheimer disease; Natural bioactives; Cholinesterase inhibitors; Antioxidants; Chimeric compounds; Hepatotoxic