Sharma_2026_RSC.Adv__

Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder involving amyloid-beta (Abeta) aggregation, cholinergic dysfunction, oxidative stress, mitochondrial impairment, and progressive neuronal loss. Consequently, the development of multi-target-directed ligands (MTDLs) capable of modulating multiple pathological pathways simultaneously has emerged as a promising therapeutic strategy. In this context, the present study describes the design, synthesis, and biological evaluation of a novel series of pyrano[3,2-c]coumarin derivatives 4a-n as dual Abeta(42) and acetylcholinesterase (AChE) targeting anti-AD agents. Compounds 4a-n showed significant protection by inhibiting tissue specific Abeta(42) aggregation in a transgenic AD model of Drosophila. In particular, compounds 4g and 4i were identified as potential lead compounds for targeting AD. These compounds inhibited endogenous Abeta(42) aggregation and exhibited a significant rescue of eye phenotypes at respective effective concentrations (ECs) (4g, 46% rescue at EC = 250 microM and 4i, 65% rescue at EC = 50 microM). Furthermore, compounds 4g and 4i effectively reduced lipid-peroxidation, which was determined by assessing thiobarbituric acid reactive substances (TBARS) levels, at 25 and 50 microM, respectively, and reactive oxygen species (ROS). Compounds 4g and 4i also exhibited AChE inhibitory activity, with IC(50) values of 0.02652 and 0.0268 microM, respectively. In silico molecular docking studies of 4i with Abeta(42) (PDB ID: 1IYT) and AChE (PDB ID: 4EY4) also corroborated their anti-AD activity. Therefore, the present study indicated these compounds, especially 4i, could be promising lead candidates for AD drug development.