Design, Synthesis, and AChE Inhibition of 4-Amino Derivatives: Molecular Docking and Biological Evaluation

Abstract

Substituted tetrahydroquinoline (THQ) derivatives were systematically designed and synthesized via a three-component Povarov reaction, employing N-vinyl carbamate, organocatalyzed substituted anilines, and benzaldehyde derivatives. The resulting THQ derivatives demonstrated a diverse range of functional groups, which potentially broadens their applicability. These compounds were rigorously characterized using various spectroscopic techniques to verify their structures. Subsequent bioevaluation of the synthesized THQs revealed their inhibitory activity against acetylcholinesterase (AChE), highlighting their potential as therapeutic agents for neurodegenerative diseases. All synthesized THQs exhibited IC50 values ranging from 0.22 to 0.36 mu M, which are lower than the IC50 value of the standard compound tacrine (0.77 mu M). The Ki values for the THQs against AChE ranged from 0.370 +/- 0.330 to 1.30 +/- 0.715 mu M. Additionally, molecular docking studies of the THQ-AChE complexes yielded binding scores between -10.8 and -12.4 kcal/mol. The structure-activity relationship (SAR) analysis underscores the significance of THQ structures in medicinal chemistry. These findings suggest that the structural insights gained from this study will be valuable for the future design and synthesis of potent AChE inhibitors.