Design, Synthesis and Biological Evaluation and Molecular Docking Study of (Z)-7-Nitro-1-Phenyl-3-((2-((1-Phenylethylidene) Amino) Ethyl) Amino) Quinoxalin-2(1H)-One Derivatives
F. O. Taiwo *
Department of Chemistry, Obafemi Awolowo University, Osun, Nigeria.
O. B. Omoyeni
Department of Chemistry, Ekiti state University, Ekiti, Nigeria.
I. J. Olawuni
Department of Biochemistry and Molecular Biology, Obafemi Awolowo University, Osun, Nigeria.
E. G. Fakola
Department of Chemistry, Obafemi Awolowo University, Osun, Nigeria.
Craig A. Obafemi
Department of Chemistry, Obafemi Awolowo University, Osun, Nigeria.
*Author to whom correspondence should be addressed.
Abstract
Aims: To synthesize (Z)-7-nitro-1-phenyl-3-((2-((1-phenylethylidene)amino)ethyl)amino)quinoxalin-2(1H)-one derivatives and evaluate their possible biological properties.
Methods: The substituted (Z)-7-nitro-1-phenyl-3-((2-((1-phenylethylidene)amino)ethyl)amino)quinoxalin-2(1H)-one derivatives were synthesized by reacting 3-((2-aminoethyl)amino)-7-nitro-1-phenylquinoxalin-2(1H)-one with different substituted aromatic ketones. The synthesized compounds were characterized using nuclear magnetic resonance (NMR) spectroscopy. Their acetylcholinesterase and butyrylcholinesterase inhibitory activities were evaluated spectrophotometrically based on the enzymatic hydrolysis of acetylthiocholine iodide and butyrylcholine chloride. Molecular docking was performed for compounds 1(a-g) against the three-dimensional structure of recombinant human acetylcholinesterase (PDB ID: 4EY7).
Results: Compounds 1e (IC50 = 0.04 ± 0.01 µM) and 1f (IC50 = 0.75 ± 0.06 µM) were the most active acetylcholinesterase inhibitors, while compounds 1b (IC50 = 0.06 ± 0.02 µM) and 1f (IC50 = 0.84 ± 0.02 µM) showed the strongest butyrylcholinesterase inhibition among the reported compounds. The docking results revealed several interactions between ligands 1(a-g) and the protein binding pocket, highlighting the roles of specific amino acid residues and interaction types in stabilising the complexes. Each ligand displayed a distinct interaction profile contributing to its predicted binding affinity and specificity.
Conclusion: The acetylcholinesterase and butyrylcholinesterase inhibitory activities of the synthesized compounds, together with their docking profiles, support further investigation of this derivative series as potential cholinesterase inhibitors.
Keywords: Alzheimer's disease, schiff base, acetylcholinesterase, butyryl cholinesterase, molecular docking, quinoxaline