Quinindoline-Based Hybrid Compounds as New Inhibitors of Acetylcholinesterase: An In Vitro and Molecular Dynamics Simulations Study

This study introduces a group of substituted pyrazolo[4,5-a]quinindolines and imidazo[4,5-a]quinindolines as potent inhibitors of acetylcholinesterase (AChE). The compounds were synthesized through a one-pot reaction of 1-alkyl-5-nitro-1H-indazole and 1-alkyl-5-nitro-1H-benzimidazole derivatives with 2-(1-alkyl-1H-3-indolyl)acetonitriles in alkaline conditions. Experimental methods such as FT-IR, MS, ¹H and ¹³C NMR spectral analysis were used to characterize the newly synthesized compounds. The catalytic activity of the enzyme was evaluated in the presence of pyrazolo[4,5-a]quinindolines and imidazo[4,5-a]quinindolines, and the mixed inhibition model determined the reversible enzyme-inhibitor complex’s inhibition constants to be between 0.069‒0.116 mM. Also, molecular modeling techniques were used to identify the specific amino acid residues in the active site of the enzyme that interact with certain ligands. The presence of these ligands caused some regions of the AChE residues to become less flexible. The analysis revealed that the ligands bind with the active site of the AChE enzyme.