Synthesis of Galanthamine-Indanone hybrid derivative as AntiAlzheimer’s disease (AD)

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, memory impairment, and behavioral abnormalities. Despite the availability of symptomatic treatments, there is still no effective cure for the disease. Galanthamine, a well-known acetylcholinesterase (AChE) inhibitor, has shown clinical benefits in improving cholinergic neurotransmission; however, its therapeutic application is limited by toxicity and side effects. The present study focuses on the design and synthesis of novel peptide-galanthamine derivatives with the objective of developing safer and more potent anti-Alzheimer agents. These derivatives were synthesized in solution using the fragment condensation technique and structurally characterized by melting point determination, nuclear magnetic resonance (NMR) spectroscopy, and mass spectral analysis. Acute toxicity studies were performed in mice using standard experimental protocols to evaluate their safety profile. In the synthesized compounds, galanthamine was chemically linked to an indanone moiety through a piperazine linker, resulting in multifunctional analogues with enhanced pharmacological potential. The newly developed derivatives exhibited significant acetylcholinesterase inhibitory activity and were also expected to possess inhibitory effects against β-secretase, a key enzyme involved in amyloid-β plaque formation in Alzheimer’s disease. The incorporation of the indanone ring provided a dual mechanism of action, contributing to improved anti-Alzheimer activity. Behavioral assessments demonstrated enhanced cognitive performance, while biochemical investigations revealed favorable neuroprotective effects. Furthermore, hepatic dysfunction parameters indicated reduced toxicity compared to the parent drug, galanthamine. Overall, the synthesized peptide-galanthamine derivatives displayed superior potency, efficacy, and safety, highlighting their potential as promising multifunctional therapeutic candidates for the management and treatment of Alzheimer’s disease.