Synthesis and Molecular Modeling of Novel 3,5-Bis(trifluoromethyl) benzylamino Benzamides as Potential CETP Inhibitors

Abstract

Background: There is an alarming spread of cases of lipid disorders in the world that occur due to harmful lifestyle habits, hereditary risk influences, or as a result of other illnesses or medicines. Cholesteryl Ester Transfer Protein (CETP) is a 476-residue lipophilic glycoprotein that helps in the transport of cholesteryl ester and phospholipids from the atheroprotective HDL to the proatherogenic LDL and VLDL. Inhibition of CETP leads to elevation of HDL cholesterol and reduction of LDL cholesterol and triglycerides; therefore, it is considered a good target for the treatment of hyperlipidemia and its comorbidities.

Objective: In this research, synthesis, characterization, molecular modeling, and biological evaluation of eight 3,5-bis(trifluoromethyl)benzylamino benzamides 9a-d and 10a-d were carried out.

Methods: The synthesized molecules were characterized using ¹H-NMR, ¹³C-NMR, IR, and HR-MS. They were biologically tested in vitro to estimate their CETP inhibitory activity.

Results: These compounds offered inhibitory effectiveness ranging from 42.2% to 100% at a concentration of 10 μM. Compounds bearing unsubstituted three aromatic rings (9a) or ortho-CF₃ substituted (9b) were the most effective compounds among their analogs and showed IC₅₀ values of 1.36 and 0.69 μM, respectively. The high docking scores of 9a-d and 10a-d against 4EWS imply that they might be possible CETP inhibitors. Pharmacophore mapping results demonstrate that the series approves the fingerprint of CETP active inhibitors and therefore explains their high binding affinity against CETP binding site.

Conclusion: This work concludes that 3,5-bis(trifluoromethyl)benzylamino benzamides can serve as a promising CETP inhibitor lead compound.

Keywords: 3; 5-bis(trifluoromethyl)benzylamino; Benzamides; CETP inhibitors; HDL; induced-fit docking; pharmacophore.