Discovery and development of multi‐target potential of flavonoids as potent acetylcholinesterase inhibitors and anti‐amnestic agents

Abstract

AbstractBackgroundMulti‐target compounds comprise a novel class of therapeutic agents for the treatment of multi‐factorial diseases like Alzheimer’s disease (AD). Following this approach, a new series of flavones were designed, synthesized and biologically evaluated against acetylcholinesterase (AChE), advanced glycation end products formation (AGEs) with additional free radical scavenging activity.MethodOn the basis of proposed hypothesis, 33 flavone derivatives were designed and subsequently synthesized and were primarily evaluated for in vitro AChE inhibitory, AGEs inhibitory and anti‐oxidative activity and prominent compounds further evaluated by in vivo anti‐amnestic activity. After that, molecular docking and Molecular dynamic simulations (MD) were carried out for the most potent compounds to study protein‐ligand interactions.ResultThe in vitro studies showed that the majority of synthesized derivatives inhibited acetylcholinesterase (AChE) with IC50 values in the nanomolar range. Additionally, these compounds also exhibited greater ability to inhibit advanced glycation end products formation in micromolar range with additional radical scavenging property in nanomolar range. The most active compounds were also ameliorated scopolamine‐induced amnesia in mice in terms of restoration of time spent in target quadrant (TSTQ) and escape latency time (ELT). Moreover, the molecular docking study displayed that most potent compounds simultaneously bind to catalytic active site (CAS) and peripheral anionic site (PAS) of AChE.ConclusionIn conclusions, the results support the proposed hypothesis that newly designed multi‐target flavones have the ability to act on different targets or exhibit multiple pharmacological activities related to Alzheimer’s disease. Thus, flavones might be the promising lead compound as potential multi‐target anti‐Alzheimer’s agents.