CETP Inhibitory Activity of Chlorobenzyl Benzamides: QPLD Docking, Pharmacophore Mapping, and Synthesis (E-pub Ahead of Print)
Reema Abu Khalaf,
Hamada Abd El-Aziz,
Ghassan Abu Sheikha.
Background: Elevated levels of serum LDL and total cholesterol are considered important
risk factors for the development of atherosclerosis. Cholesteryl ester transfer protein inhibition
raises HDL levels and reduces atherosclerotic lesions.
Objective: Consequently, there is a great interest in developing new CETP inhibitors.
Method: Herein, synthesis of four chlorobenzyl benzamides 8a-d that aim at CETP inhibition was
Results: Benzamide 8a showed the best CETP inhibitory activity with an IC50 of 1.6 μM. In vitro
biological data shows that the presence of p-trifluoromethoxy group enhances CETP inhibitory
activity more than m-trifluoromethyl groups. QPLD docking shows that the verified compounds
accommodate the binding cleft of CETP and are enclosed by hydrophobic lining. The scaffold of
8a-d matches the pharmacophoric points of CETP inhibitors; particularly hydrophobic and aromatic
Conclusion: Future structural modification is needed to improve CETP inhibitory activity and to
enhance understanding of the structure-activity relationship.
Keywords: Atherosclerosis, CETP inhibitors, Chlorobenzyl benzamides, Docking, QPLD, Pharmacophore mapping.
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