Design, synthesis, and computational insights into 3-acetyl-8-methoxy coumarin hybrids as potential anti-alzheimer’s agents

The most prevalent degenerative brain disease, Alzheimer's disease (AD), is characterized by cognitive function impairment. The ability to code new memories is lost in AD patients, and their lives are very challenging. Inhibitors of cholinesterase (ChE) and monoamine oxidase (MAO) have drawn interest as potential therapies for AD. To combat Alzheimer's disease (AD), a new class of Coumarin-hydrazone hybrids has been synthesized 3(a-m). Compounds 3a, 3e, and 3l exhibited significant acetylcholinesterase (AChE) inhibitory activity with low IC₅₀ values of 7.40 ± 0.14 µM, 8.01 ± 0.70 µM, and 8.54 ± 1.01 µM, respectively. Additionally, these compounds, along with 3k, demonstrated potent butyrylcholinesterase (BChE) inhibition, with IC₅₀ values from 65.41 ± 4.55 µM to 74.98 ± 5.30 µM, highlighting their dual cholinesterase inhibitory potential. Compound like 3a (1.44 ± 0.03 µM), 3e (1.51 ± 0.13 µM), and 3l (1.65 ± 0.03 µM) display robust MAO-A inhibition, suggesting high potency. To see how the most potent inhibitor chemicals affected the substrate-enzyme relationship, enzyme kinetic tests were conducted in addition to enzyme inhibition investigations. Compound 3e may function as a dual binding site AChE inhibitor, according to docking studies in addition to in vitro testing.