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

Abstract

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.

Supplementary Information: The online version contains supplementary material available at 10.1038/s41598-025-32012-y.

Keywords: Multi-target-directed ligands; Neurodegenerative disorders; Quinoline-8-sulfonate; Thiosemicarbazones.

Fig. 1

Reported thiosemicarbazones as potential anti-Alzheimer agents^–.

Fig. 2

Synthetic Route of 4-phenyl-quinoline-8-sulfonate based thiosemicarbazones.

Fig. 3

Illustration of structural diversity and the influence of chemical modifications on biological activity.

Fig. 4

Overlap of docked conformations of AChE inhibitors with the co-crystallized inhibitor dihydrotanshinone I (represented in black).

Fig. 5

Binding site interactions of docked conformations of AChE inhibitors (A) 5c, (B) 5e and (C) 5 g indicating similar binding orientation and interactions.

Fig. 6

Summary of binding site interactions of AChE inhibitors 5c, 5e and 5 g.

Fig. 7

Overlap of docked conformations of BChE inhibitors 5b, 5c and 5 g with the co-crystallized inhibitor tacrine (represented in black).

Fig. 8

Binding site interactions of docked conformations of BChE inhibitors (A) 5b, (B) 5c and (C) 5 g indicating similar binding orientation and interactions.

Fig. 9

Summary of binding site interactions of BChE inhibitors 5b, 5c and 5 g.

Fig. 10

Overlap of docked conformations of MAO A inhibitors 5c, 5e and 5q with the co-crystallized inhibitor harmine (represented in black) and FAD co-factor (in blue), (A) without surface representation, (B) with surface representation, (C) zoomed-in region showing inhibitors are oriented slightly outward, hindering/covering the opening of the binding site as compared to harmine which is snugged inside the active site.

Fig. 11

Binding site interactions of docked conformations of MAO A Inhibitors (A) 5c, (B) 5e and (C) 5q.

Fig. 12

Summary of binding site interactions of MAO A inhibitors 5c, 5e and 5q (where, n = 0, 1).

Fig. 13

MD simulation studies of complex of 5e with AChE for 100ns, (A) RMSD plot; (B) Protein RMSF graph; (C) Ligand RMSF graph and (D) protein ligand contacts.

Fig. 14

Ligand Protein Contacts, and Ligand Torsion Profile of 5e with AChE.

Fig. 15

MD simulation studies of complex of 5 g with BChE for 100ns, (A) RMSD plot; (B) Protein RMSF graph; (C) Ligand RMSF graph and (D) protein ligand contacts.

Fig. 16

Ligand Protein Contacts (left), and Ligand Torsion Profile (right) of 5 g with BChE.

Fig. 17

MD simulation of 5c with MAO A for 100ns, (A) RMSD plot; (B) Protein RMSF graph; (C) Ligand RMSF graph and (D) protein ligand contacts.

Fig. 18

Ligand Protein Contacts, and Ligand Torsion Profile of 5c with MAO A.