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Issue 3, 2018
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5,6-Benzoflavones as cholesterol esterase inhibitors: synthesis, biological evaluation and docking studies

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Abstract

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 (B-10 to B-16) exhibited above 90 percent inhibition against CEase in an in vitro enzymatic assay. Compound B-16 showed the most promising activity with an IC50 value of 0.73 nM against cholesterol esterase. To determine the type of inhibition, enzyme kinetic studies were carried out for B-16, which revealed its mixed-type inhibition approach. Moreover, to figure out the key binding interactions of B-16 with the amino acid residues of the enzyme's active site, molecular protein–ligand docking studies were also performed. B-16 completely blocks the catalytic assembly of CEase and prevents it from participating in the ester hydrolysis mechanism. The favorable binding conformation of B-16 suggests its prevailing role as a CEase inhibitor. Overall, the study showed that the cis-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.

Graphical abstract: 5,6-Benzoflavones as cholesterol esterase inhibitors: synthesis, biological evaluation and docking studies

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Publication details

The article was received on 06 Nov 2017, accepted on 04 Jan 2018 and first published on 19 Jan 2018


Article type: Research Article
DOI: 10.1039/C7MD00565B
Citation: Med. Chem. Commun., 2018,9, 490-502
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    5,6-Benzoflavones as cholesterol esterase inhibitors: synthesis, biological evaluation and docking studies

    J. V. Singh, A. Kaur, K. Bhagat, M. K. Gupta, M. Singh, H. Singh and P. M. S. Bedi, Med. Chem. Commun., 2018, 9, 490
    DOI: 10.1039/C7MD00565B

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