Pristine 2-chloroquinoline-based-thiosemicarbazones as multitarget agents against alzheimer's disease: In vitro and in silico studies of monoamine oxidase (MAO) and cholinesterase (ChE) inhibitors

Neurodegenerative diseases can be treated more effectively with multitarget approaches. monoamine oxidases (MAOs) acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) are promising agents for cognitive decline. Here, a series of novel 2-chloroquinoline-3-carbaldehyd thiosemicarbazone derivatives (3a-r) were synthesized via a single-pot reaction. In-vitro testing results showed four compound 3c, 3o, 3 g and 3l having chloro, fluoro, methyl and ethyl functional groups showed high potency against MAO-A, MAO-B, AChE and BChE, with an IC50 value 0.549 ± 0.045, 0.340 ± 0.02, 0.280 ± 0.135 and 2.77 ± 0.62 µM, respectively. Compounds 3 g exhibited maximum inhibitory potential against all four targeted enzymes. Density functional theory (DFT) was used to evaluate the reaction profiles of the potent derivatives. We found that compounds 3c, 3o, 3l, and 3 g exhibited strong reactivity because their LUMO/HOMO energy gaps were narrow. In addition, the molecular docking studies revealed excellent docking scores, ligands were well accommodated in the active site of targeted enzymes and produced stable protein-ligand complexes. The stability of the protein-ligand complex was confirmed by molecular dynamic (MD) simulations which revealed stable and equilibrated protein-ligand complexes. While compounds 3p, 3q and 3r were less effective than the whole series against the targeted enzymes. This integrated approach enhances the findings' comprehensiveness and reliability. The finding of In-vitro and In-silico studies suggested compound 3 g as a promising multi-targeted compound that can be act as a molecule for AD treatment.