Design, synthesis, and multi-target evaluation of 4-phenyl quinoline-8-sulfonate thiosemicarbazones as potential anti-Alzheimer agents.

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder marked by cognitive and memory decline. A novel series of 4-phenyl-quinoline-8-sulfonate-based thiosemicarbazones 5(a–r) were synthesized, characterized by some spectroscopic techniques and evaluated for their potential as anti-Alzheimer agents. Among them, compound 5c, bearing an o-fluoro phenyl group, showed multi-target inhibition with an IC₅₀ values of 78.07 ± 3.14 µM acetylcholinesterase (AChE), 22.63 ± 2.81 µM butyrylcholinesterase (BChE) and 0.84 ± 0.01 µM monoamine oxidase A (MAO-A), showing higher inhibitory potential than the reference clorgyline with IC₅₀ value 66.20 ± 4.01 µM. Other compounds, such as 5e, 5 g, 5b and 5q also exhibited significant inhibition across targets. Molecular docking confirmed strong binding interactions, particularly with the catalytic sites of AChE, BChE and MAO-A. These findings highlight 5c as a promising lead for multi-targeted AD therapy.