title: Benzoflavones as cholesterol esterase inhibitors: Synthesis, biological evaluation and docking studies.
abstract: 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 IC50value 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.
authors.affiliation: Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar, Punjab 143005, India.
authors.forename: Harbinder
authors.initials: H
authors.lastname: Singh
authors.affiliation: Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar, Punjab 143005, India.
authors.forename: Jatinder Vir
authors.initials: JV
authors.lastname: Singh
authors.affiliation: Lloyd Institute of Management and Technology, Greater Noida, UP, India.
authors.forename: Manish K
authors.initials: MK
authors.lastname: Gupta
authors.affiliation: Department of Chemistry, Guru Nanak Dev University, Amritsar, Punjab 143005, India.
authors.forename: Palwinder
authors.initials: P
authors.lastname: Singh
authors.affiliation: Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar, Punjab 143005, India. Electronic address: ss.gq2009@gmail.com.
authors.forename: Sahil
authors.initials: S
authors.lastname: Sharma
authors.affiliation: Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar, Punjab 143005, India.
authors.forename: Kunal
authors.initials: K
authors.lastname: Nepali
authors.affiliation: Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar, Punjab 143005, India.
authors.forename: Preet Mohinder S
authors.initials: PMS
authors.lastname: Bedi
mesh_terms: D001571:Benzoflavones / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D020134:Catalytic Domain; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D057927:Hydrophobic and Hydrophilic Interactions; D020128:Inhibitory Concentration 50; D007700:Kinetics; D062105:Molecular Docking Simulation; D011485:Protein Binding; D002787:Sterol Esterase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D001571:Benzoflavones; D004791:Enzyme Inhibitors; D002787:Sterol Esterase
keywords: Baker Venkataraman rearrangement; Benzoflavone; Cholesterol esterase inhibition; Docking studies; Enzyme kinetics