Synthesis, Characterisation and Docking Studies of Thioxoquinoline Derivatives as Potential Anti-Alzheimer Agents.

Background: Alzheimer's Disease (AD) is related to the total loss of presynaptic neurotransmitters of the cholinergic system in regions of the brain related to memory. Approximately 15% of the population beyond the age of 65 years are suffering from dementia due to AD and the rate is rising exponentially with age.

Objective: The objective of this research was the synthesis of a series of 1-(4-substituted-2- thioxoquinolin-1(2H)-yl)-2-substituted ethanoneV (a-c(1-4)) by undergoing acetylation at the nitrogen of 4-hydroxyquinolin-2-(1H)-one and replacing its oxygen atom with sulphur moiety via the process of thionation. To carry out-docking studies of the title compounds were carried out using Molegro Virtual Docker (MVD-2013, 6.0) software and in-vitro screening of anti-alzheimer's activity by Ellman assay method.

Methods: The synthesis of the title compounds was carried out via the sequential reaction from the initial dianilide to ring closure to the substituted quinoline-2-ones using polyphosphoric acid as a cyclising agent. These substituted quinoline-2-ones on thionation by phosphorous pentasulphide in aluminium trioxide gave quinoline-2-thiones and on further condensation with chloroacetyl chloride, they resulted in compounds with a leaving group. Nucleophilic substitution reaction of chloroacetylquinoline- 2-thiones with secondary amines resulted in the title compounds 1-(4-substituted-2- thioxoquinolin-1(2H)-yl)-2-substituted ethanone V(a-c(1-4)). The pharmacophore mapping of synthesized compounds was performed by using Molegro Virtual Docker (MVD-2013,6.0). The title compounds were tested for their in vitro anti-Alzheimer's activity using the Ellman assay method.

Results: All the synthesized compounds were characterized by IR, ¹H NMR, ¹³C NMR, and Mass spectral data. Docking studies of all the synthesized compounds were carried out using a structural mechanism for the inhibition of CDK5-p25 by roscovitine, aloisine, and indirubin (PDB ID: 1UNG), showed favourable results, with compound (Vb3) showing a MolDock score of -85.9788 that was comparable to that of the active ligand (ALH_1288 [B]) with MolDock score of - 87.7609.

Conclusion: The synthesized derivatives possessed the potential to bind with some of the amino acid residues of the active site. Compound 2-(6-chloro-4-hydroxy-2-thioxoquinolin-1(2H)-yl-1-piperazin- 1-ethanone (Vb3) was found to be the most active among the synthesized derivatives, with IC₅₀ values of 32 ± 0.1681. All the synthesized compounds showed potent to moderate activity in comparison to the reference standard donepezil.