Structure-Based Scaffold Repurposing toward the Discovery of Novel Cholinesterase Inhibitors

Area of Science:

• Medicinal Chemistry
• Neuroscience
• Drug Discovery

Background:

• Cholinesterases (ChE) are key therapeutic targets for Alzheimer's disease (AD).
• Developing novel ChE inhibitors remains a critical area of research for AD treatment.

Purpose of the Study:

• To identify novel cholinesterase inhibitors using a structure-based scaffold repurposing approach.
• To evaluate the potential of repurposed compounds as drug candidates for Alzheimer's disease.

Main Methods:

• Utilized a structure-based scaffold repurposing strategy.
• Screened a DNA gyrase inhibitor library for ChE inhibitory activity.
• Assessed compound potency via IC50 values for AChE and BuChE.
• Analyzed molecular interactions using docking studies.
• Evaluated in vitro cytotoxicity and in silico ADME properties.

Main Results:

• Discovered six novel ChE inhibitors from a DNA gyrase inhibitor library.
• Identified compounds 3 and 18 as the most potent inhibitors of AChE and BuChE, respectively.
• Compound 3 demonstrated H-bond and π-π stacking interactions with AChE.
• Compound 18 exhibited favorable binding within the BuChE active site.
• Compounds 3 and 18 showed promising in vitro and in silico safety and pharmacokinetic profiles.

Conclusions:

• Repurposed scaffolds 3 and 18 are effective inhibitors of AChE and BuChE.
• These compounds represent promising leads for the development of novel Alzheimer's disease therapeutics.
• Further development of these ChE inhibitors is warranted based on their potency and favorable properties.