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In a continued effort to develop potent cholesterol esterase (CEase) inhibitors, a series of 5,6-benzoflavone derivatives was rationally designed and synthesized by changing the position of the benzene ring attached to the flavone skeleton in previously reported 7,8-benzoflavones. All the synthesized compounds were checked for their inhibitory potential against cholesterol esterase (CEase) using a spectrophotometric assay. Among the series of forty compounds, seven derivatives (- to -) exhibited above 90 percent inhibition against CEase in an enzymatic assay. Compound- showed the most promising activity with an IC value of 0.73 nM against cholesterol esterase. To determine the type of inhibition, enzyme kinetic studies were carried out for -, which revealed its mixed-type inhibition approach. Moreover, to figure out the key binding interactions of - with the amino acid residues of the enzyme's active site, molecular protein-ligand docking studies were also performed. - completely blocks the catalytic assembly of CEase and prevents it from participating in the ester hydrolysis mechanism. The favorable binding conformation of - suggests its prevailing role as a CEase inhibitor. Overall, the study showed that the -orientation of ring A with respect to the carbonyl group of ring C is responsible for the potent CEase inhibitory activity of the newly synthesized compounds.

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