Design, synthesis and biological evaluation of naphthalene-pyrazoline derivatives as neuroprotective agents for alzheimer's disease

Abstract

Alzheimer's disease (AD) is a progressive neurological disorder that leads to memory loss and cognitive deterioration, primarily affecting the elderly population. The current therapeutic approaches are insufficient and primarily focus on alternative symptoms rather than disease modification. Acetylcholinesterase (AChE) inhibitors are a class of drugs that have shown promise in alleviating the cognitive symptoms of AD by preventing the breakdown of acetylcholine, thereby enhancing cholinergic transmission. This study presents the design, synthesis, and assessment of ten novel naphthalene-pyrazoline derivatives as AChE inhibitors. Each compound was synthesized using a rational drug design approach, targeting key structural features necessary for effective AChE inhibition. The inhibitory activities of the synthesized compounds were assessed by in vitro study where out of all compounds AJ-a showed potency with IC₅₀ value of 56.15 ± 1.84 μM. The in vivo studies were also performed using zebrafish model, behavior parameters such as T-maze and Novel diving test. Molecular docking studies were performed to analyse the binding interactions between the inhibitors and the active site of AChE. The docking results provided insights into the key binding interactions and conformations contributing to the inhibitory activity. Compound AJ-a had the docking score of −12.436 kcal/mol. These results highlight the potential of the novel compounds as promising candidates for further development in the treatment of AD.