Synthesis of Flavonoid/Sulfonamide Hybrid Molecules as Potential Inhibitors of Cholinesterases: In Vitro, Molecular Docking, Molecular Dynamic and DFT Studies

Abstract Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) belong to the serine hydrolase enzyme family and has been implicated to have a crucial role in the pathogenesis of Alzheimer's disease (AD). Generally, treatment strategies for AD has focused on the development of inhibitors of these enzymes. In light of this, a series of novel N ‐(4‐sulfamoylphenyl)‐3‐methylflavone‐8‐carboxamide compounds were synthesized and their inhibition potentials on AChE and BChE were investigated. The results of the inhibition assay revealed that N ‐(2,6‐dichloro‐4‐sulfamoylphenyl)‐3‐methylflavone‐8‐carboxamide was the most active inhibitor for AChE and BChE with K i values of 4.2 nM and 0.15 μM, respectively. Compared to the standard drug rivastigmine all the synthesized compounds showed better AChE inhibition properties, while the BChE inhibition was comparable to the drug. The results indicate that N ‐(2,6‐dichloro‐4‐sulfamoylphenyl)‐3‐methylflavone‐8‐carboxamide can be considered for further drug design studies and thus DFT analyses were conducted to clarify the electronic structures of the compound while molecular docking was performed to determine the binding affinities of the compound to target proteins. Lastly, molecular dynamics (MD) simulations were conducted to assess the time‐dependent behavioral changes of the complexes.