Benzoflavones as cholesterol esterase inhibitors: Synthesis, biological evaluation and docking studies.

Harbinder Singh, Jatinder Vir Singh, Manish K Gupta, Palwinder Singh, Sahil Sharma, Kunal Nepali, Preet Mohinder S Bedi

Bioorganic & medicinal chemistry letters 2017 Feb 15

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A library of forty 7,8-benzoflavone derivatives was synthesized and evaluated for their inhibitory potential against cholesterol esterase (CEase). Among all the synthesized compounds seven benzoflavone derivatives (A-7, A-8, A-10, A-11, A-12, A-13, A-15) exhibited significant inhibition against CEase in in vitro enzymatic assay. Compound A-12 showed the most promising activity with IC50 value of 0.78nM against cholesterol esterase. Enzyme kinetic studies carried out for A-12, revealed its mixed-type inhibition approach. Molecular protein-ligand docking studies were also performed to figure out the key binding interactions of A-12 with the amino acid residues of the enzyme's active site. The A-12 fits well at the catalytic site and is stabilized by hydrophobic interactions. It completely blocks the catalytic assembly of CEase and prevents it to participate in ester hydrolysis mechanism. The favorable binding conformation of A-12 suggests its prevailing role as CEase inhibitor. Copyright © 2017 Elsevier Ltd. All rights reserved.

Citation

Harbinder Singh, Jatinder Vir Singh, Manish K Gupta, Palwinder Singh, Sahil Sharma, Kunal Nepali, Preet Mohinder S Bedi. Benzoflavones as cholesterol esterase inhibitors: Synthesis, biological evaluation and docking studies. Bioorganic & medicinal chemistry letters. 2017 Feb 15;27(4):850-854