Exploring 3-Benzyloxyflavones as new lead cholinesterase inhibitors: synthesis, structure–activity relationship and molecular modelling simulations

In this protocol, a series of 3-benzyloxyflavone derivatives have been designed, synthesized, characterized and investigated <i>in vitro</i> as cholinesterase inhibitors. The findings showed that all the synthesized target compounds (<b>1–10</b>) are potent dual inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes with varying IC₅₀ values. In comparison, they are more active against AChE than BChE. Remarkably, amongst the series, the compound <b>2</b> was identified as the most active inhibitor of both AChE (IC₅₀ = 0.05 ± 0.01 μM) and BChE (IC₅₀ = 0.09 ± 0.02 μM) relative to the standard Donepezil (IC₅₀ = 0.09 ± 0.01 for AChE and 0.13 ± 0.04 μM for BChE). Moreover, the derivatives <b>5</b> (IC₅₀ = 0.07 ± 0.02 μM) and <b>10</b> (0.08 ± 0.02 μM) exhibited the highest selective inhibition against AChE as compared to the standard. Preliminary structure-activity relationship was established and thus found that cholinesterase inhibitory activities of these compounds are highly dependent on the nature and position of various substituents on Ring-B of the 3-Benzyloxyflavone scaffolds. In order to find out the nature of binding interactions of the compounds and active sites of the enzymes, molecular docking studies were carried out. HIGHLIGHTS3-benzyloxyflavone analogues were designed, synthesized and characterized.The target molecules (<b>1–10</b>) were evaluated for their inhibitory potential against AChE and BChE inhibitory activities.Limited structure-activity relationship was developed based on the different substituent patterns on aryl part.Molecular docking studies were conducted to correlate the <i>in vitro</i> results and to identify possible mode of interactions at the active pocket site of the enzyme. 3-benzyloxyflavone analogues were designed, synthesized and characterized. The target molecules (<b>1–10</b>) were evaluated for their inhibitory potential against AChE and BChE inhibitory activities. Limited structure-activity relationship was developed based on the different substituent patterns on aryl part. Molecular docking studies were conducted to correlate the <i>in vitro</i> results and to identify possible mode of interactions at the active pocket site of the enzyme. Communicated by Ramaswamy H. Sarma