Novel Phenolic Hydrazide–Hydrazones as Multi-Target Anti-Alzheimer Agents: Docking and ADMET Studies

Abstract

Alzheimer's disease (AD) is a neurodegenerative ailment characterised by increasing cognitive impairment, memory loss and decreased cholinergic neurotransmission. Acetylcholinesterase (AChE) inhibitors are still one of the most efficient therapeutic strategies for symptomatic treatment of AD; nevertheless, the existing medications have significant drawbacks such as unpleasant effects and limited efficiency. Herein, creation and evaluation of a series of new phenolic hydrazide-hydrazone derivatives as possible AChE inhibitors on the basis of molecular docking and ADMET investigations are reported. Ten ligands (A01–A10) were rationally developed from previously described hydrazide–hydrazone pharmacophores with antioxidant and neuroprotective effects. Molecular docking investigations were conducted against crystal structure of AChE protein (PDB ID: 7E3H) using PyRx and AutoDock Vina software . The proposed compounds exhibited good binding affinity towards the active site of AChE with docking scores ranging from −10.4 to −11.8 kcal/mol. Among the synthesised analogues, A04, A06 and A10 showed superior docking scores and favourable interactions with important amino acid residues such as TYR337, TYR341 and GLY122 equivalent to the standard medicine donepezil (-11.9 kcal/mol). ADMET analysis using SwissADME showed adequate drug similarity, favourable pharmacokinetic features and conformity to Lipinski’s criterion for majority of the substances. The phenolic moiety may also have antioxidant and neuroprotective benefits. In conclusion, the present investigation reveals that phenolic hydrazide-hydrazone derivatives have potential anti-Alzheimer properties and they might be used as lead compounds for further synthesis, biological assessment and creation of safer and more efficient AChE inhibitors.