Cholesteryl ester transfer protein inhibitory oxoacetamido-benzamide derivatives: Glide docking, pharmacophore mapping, and synthesis

Abstract

Dyslipidemia is an abnormal lipid profile associated with many common diseases, including coronary heart disease and atherosclerosis. Cholesteryl ester transfer protein (CETP) is a hydrophobic plasma glycoprotein that is responsible for the transfer of cholesteryl ester from high-density lipoprotein athero-protective particles to pro-atherogenic very low-density lipoprotein and low-density lipoprotein particles. The requirement for new CETP inhibitors, which block this process has driven our current work. Here, the synthesis as well as the ligand-based and structure-based design of seven oxoacetamido-benzamides 9a-g with CETP inhibitory activity is described. An in vitro study demonstrated that most of these compounds have appreciable CETP inhibitory activity. Compound 9g showed the highest inhibitory activity against CETP with an IC 50 of 0.96 μM. Glide docking data for compounds 9a-g and torcetrapib provide evidence that they are accommodated in the CETP active site where hydrophobic interactions drive ligand/CETP complex formation. Furthermore, compounds 9a-g match the features of known CETP active inhibitors, providing a rationale for their high docking scores against the CETP binding domain. Therefore, these oxoacetamido-benzamides show potential for use as novel CETP inhibitors.

Exploration of Potentially Bioactive Compounds from Fingerroot (Boesenbergia rotunda L.) as Inhibitor of Atherosclerosis-Related Proteins (CETP, ACAT1, OSC, sPLA2): An in silico Study

“…Bioactivity prediction of the compounds was conducted using the PASSOnline web server (http://way2drug.com/PassOnline/). Several parameters related to atherosclerosis, such as cholesterol synthesis inhibition, anti-hypercholesterolemia, anti-inflammatory, and antioxidant properties, were taken into account [16][17][18][19] .…”

Cholesteryl Ester Transfer Protein Inhibitory Activity of New 4-Bromophenethyl Benzamides

“…The methyl benzoate intermediates 5a-d were synthesized as previously described [16][17][18][19][20] and purified by column chromatography using different concentrations of cyclohexane and ethyl acetate. The preparation of the acyl intermediates 7a-d from methyl esters 5a-d was carried out as formerly stated [16][17][18][19][20].…”

“…Besides, evacetrapib study was terminated due to its low efficacy, while anacetrapib is still under further investigation [12]. Earlier our group design and synthesize different potential CETP inhibitors (Figure 2) such as: benzylideneamino methanones [13], benzyl-amino-methanones [14], N-(4-benzyloxyphenyl)-4-methyl-benzenesulfonamides, N-(4-benzylamino-phenyl)-toluene-4-sulfonic acid esters [15], chlorobenzyl benzamides [16], fluorinated benzamides [17,18], substituted benzyl benzamides [19,20] and aryl sulfonamides [21,22]. Our study aims to synthesize new benzamide analogues 9a-d by varying the substitution with different groups such as -OCF3, -CF3, and-CF2CF2H, in addition to altering the chain length at the benzyl amine side, followed by in vitro biological evaluation of the targeted compounds as CETP inhibitors.…”

Fluorinated Benzyloxalamides: Glide Docking Pharmacophore Mapping Synthesis and In Vitro Evaluation as Potential Cholesteryl Ester Transfer Protein Inhibitors

“…Commercially available CETP inhibition drug screening kit was used (BioVision, Linda Vista Avenue, USA). [51] : 3-Aminobenzoic acid (1, 2.0 g, 14.58 mmol) was dissolved in methanol (20 ml) and cooled in the ice bath. The solution was treated with oxalyl chloride (2, 2.5 ml, 29 mmol) stirred at room temperature for 20-30 min and refluxed for 24 h at 60°-70°.…”

“…Several series of CETP inhibitors were developed in our research lab including benzylideneamino-methanones [44] , benzylamino-methanones [45] , benzene sulfonamides and toluene-4-sulfonic acid esters [46] , fluorinated benzamides [47] , chlorobenzyl benzamides [48] and substituted benzamides [49][50][51] . So as to understand better the structure activity relationship of the formerly discovered hits [49] , different analogues were prepared by varying the aromatic substitution (p-CF 3 , p-OCF 2 CF 2 H) then biological activity of these compounds was evaluated.…”