Molecular Docking and Pharmacophore Modeling Studies of Fluorinated Benzamides as Potential CETP Inhibitors

Hyperlipidemia is one of the most common chronic diseases worldwide. Cholesteryl ester transfer protein (CETP) is a hydrophobic glycoprotein that facilitates the transfer of cholesteryl ester from the atheroprotective high-density lipoprotein (HDL) to the proatherogenic low-density lipoprotein (LDL) and very low-density lipoprotein (VLDL).

In this work, synthesis and characterization of five fluorinated 3-benzylamino benzamides 8a-8c, 13a and 13b that target CETP activity were carried out.

Benzamides 8b and 8a showed the highest CETP inhibitory activities with an IC50 of 0.75 μM and 4.1 μM respectively. It was found that the presence of p-OCF3 group (as in 8a-8c) enhances CETP inhibitory activity more than p-OCF2CHF2 (as in 13a and 13b) which could be attributed to the bulkiness of the tetrafluoroethoxy group hindering their proper orientation in the binding domain. Additionally m-F derivatives were found to have higher activity against CETP than p-F ones leaving the o-F analogues with the weakest anti-CETP bioactivity.

Ligand-based and structure-based drug design strategies confirm that hydrophobic interaction mediates ligand/protein complex formation and explains the activity of our verified molecules.