Synthesis, cholinesterase inhibitory activity, and integrated DFT-docking study of quinoline-pyrene hybrid molecules

Abstract

A series of novel quinoline-pyrene hybrid compounds (C1-C5) was synthesized using an efficient and versatile synthetic approach and evaluated for their inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), two key enzymes associated with Alzheimers disease. Biological assays revealed that compound C1 exhibited the most potent inhibition of AChE, with an IC50 value of 295.12 +/- 1.02 nM, while compound C3 showed the strongest inhibitory activity against BChE, with an IC50 value of 48.11 +/- 0.13 nM. To gain molecular-level insight into the observed activity trends, Density Functional Theory (DFT) calculations were performed at the B3LYP/6-311++G(d,p) level. Geometry optimization confirmed that all compounds maintain a conserved, planar aromatic framework, while molecular electrostatic potential (MEP) analysis revealed electron rich regions primarily localized on the triazole ring and central molecular cavity. Frontier molecular orbital (FMO) analysis showed that substituent variation significantly modulates HOMO and LUMO distributions, with HOMO-LUMO energy gaps in the range of 3.0-3.5 eV, indicating favorable electronic flexibility for biological interactions. Molecular docking studies against AChE and BChE demonstrated strong and stable binding of all compounds within the catalytic gorges of both enzymes, with predicted binding energies consistent with the experimental inhibition data. Key stabilizing interactions included pi-pi stacking with aromatic residues, hydrophobic contacts, and hydrogen bonding, with compound C1 showing optimal interactions in AChE and compound C4 displaying favorable binding within the larger BChE active site. Overall, the combined experimental, computational, and docking results highlight quinoline-pyrene hybrids as promising dual cholinesterase inhibitors and provide a rational basis for further optimization toward potential anti-Alzheimers therapeutics.