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

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• 作者：Harbinder Singh^a ; Jatinder Vir Singh^a ; Manish K. Gupta^b ; Palwinder Singh^c ; Sahil Sharma^a ; ^{ss.gq2009@gmail.com} ; Kunal Nepali^a ; ; Preet Mohinder S. Bedi^a ;
• 关键词：Benzoflavone ; Baker Venkataraman rearrangement ; Cholesterol esterase inhibition ; Enzyme kinetics ; Docking studies
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2017
• 出版时间：15 February 2017
• 年：2017
• 卷：27
• 期：4
• 页码：850-854
• 全文大小：1054 K
• 卷排序：27

文摘

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 0.78 nM 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.