Design, Synthesis and Molecular Docking Studies of 2-Aryl/Heteroaryl-Ethyl 6-Chloroquinoline-4-Carboxylates as Potential Antimalarial Agents

Abstract

In an effort to develop a lead antimalarial compounds, a series of novel 2-aryl/heteroarylethyl-6-chloroquinoline-4-carboxylate derivatives (2a-j) were obtained by using quinoline-4-carboxylic acid derivatives which were produced by a simple one-pot synthesis of Pfitzinger reaction of isatin with Arylketones as intermediates which were finally esterified with ethanol in the presence of concentrated sulfuric acid to get the expected ethyl-6-chloro-2-(furan-2-yl)quinoline-4-carboxylates (2a-j) with good to excellent yields. All the crude products were purified by column chromatography using silica gel (60-120 mesh, petroleum ether: ethyl acetate, 9:1 v/v), to furnish analytically pure 2-aryl/heteroaryl-ethyl-6-chloroquinoline-4-carboxylates (2a-j). Additionally, the structures of the products were confirmed by spectral analysis such as 1H NMR, 13C NMR and LCMS analysis. As Molecular docking results illustrates, the most potent ligands among the synthesized compounds are 2j and 2h. The ligand Ethyl-2-(anthracen-9-yl)-6-chloroquinoline-4-carboxylate (2j) derivative interacts with FTase receptor at the binding sites located within the active site amino acids such as ARG291, LYS294 with binding energy -10.11 kcal/mol, docking energy -11.78 kcal/mol and inhibition constant Ki= 3.88e-008 µM respectively. The another ligand 2h was also shown strong binding interaction with active site HIS248, ARG291and ARG291 with binding energy of -9.81 kcal/mol docking energy -11.27 kcal/mol and inhibition constant Ki=6.5e-008 mM respectively. In the same way ligands 2a, 2b, 2d and 2i forms four hydrogen bonding interaction with amino acids having binding energy -6.72, -6.54, -6.87 and-8.02 kcal/mol respectively, indicates more potent inhibitors of farnesyltransferase receptor. With this it was concluded that the compounds 2a-j were found to be a potent and selective FTase antagonist inhibitors. Keywords: 2-aryl/heteroaryl-ethyl6-chloroquinoline-4-carboxylates, antimalarial, molecular docking, farnesyltransferase, lipinski, ADMET.