Unveiling Piperazine-Quinoline Hybrids as Potential Multi-Target Directed Anti- Alzheimer’s Agents: Design, Synthesis and Biological Evaluation

Abstract Multi-target directed ligands (MTDLs) have recently been popularized due to their outstanding efficacy in combating the complicated features of Alzheimer's disease. This study details the synthesis of piperazine-quinoline-based MTDLs through a multicomponent Petasis reaction, targeting multiple factors such as AChE, BuChE, metal chelation to restore metal dyshomeostasis, and antioxidant activity. Some of the synthesized compounds exhibited notable inhibitory activity against AChE and BuChE enzymes at specific concentrations. Among the synthesized compounds compound ( 95 ) containing a 4-chloroaniline moiety and a 4-methoxybenzyl group displayed the most promising inhibitory activities against AChE (IC 50 3.013 µM) and BuChE (IC 50 = 3.144 µM). Compound ( 83 ) featuring 2-methoxyaniline and 4-fluorobenzyl substituents, exhibited the highest BuChE inhibition (IC 50 1.888 µM). Notably, compound ( 79 ) demonstrated 93-times higher selectivity for BuChE over AChE. Out of these compounds nine compounds were assessed for antioxidant activity, displaying significant potential at a concentration of 100 μM. Moreover, all the compounds demonstrated metal chelating activity with Cu +2 , Zn +2 , Fe +2 , Fe +3 and Al +3 . This study provides insights into the design of novel MTDLs, highlighting compound ( 95 ) as a potential candidate for Inhibiting Alzheimer's disease and emphasizing its role in the development of anti-AD medication.