Interaction of Imidazo[4,5-a]Acridines with Acetylcholinesterase

The present work deals with the synthesis, spectral characterization and the interaction of new tetracyclic imidazo[4,5-a]acridines with acetylcholinesterase (AChE) enzyme. This compound was obtained via hydrolysis in the CN group of 8-methoxy-3-methyl-3H-imidazo[4,5-a]acridine-11-carbonitrile in high yield. The target compound was synthesized from the reaction of 1-methyl-5-nitro-1H-benzo[d]imidazole with 2-(4-methoxyphenyl)acetonitrile in basic medium. The catalytic activity of AChE was investigated in the presence of title compound and inhibition constants were determined for the reversible enzyme–inhibitor complex. Based on the mixed inhibition model, inhibition constant for the title compound was 0.097 mM. Molecular modeling of the complex (ligand–enzyme) was used to determine amino acid residues of the active site involved in the interaction. In the presence of the ligand in some regions, such as residues 80 – 87, 328 – 347, 433 – 440, 484 – 492 and the N-terminal residues, the flexibility of the AChE residues has decreased. Also, the calculations show that the new ligand interacts with the active site of AChE. The Trp84, Phe330, and His440 residues play a role in this interaction. These residues are located in the cavity of the AChE binding site. Trp84 and His440 are located at the bottom of the cavity, and Phe330 occurs in the middle of the cavity. These residues exhibit hydrophobic interaction with the new ligand. Also, the ligand has altered the secondary structure of AChE. The helical secondary structure of AChE is most affected by the ligand.