Title:Fluorinated Diaryl Sulfonamides: Molecular Modeling, Synthesis, and
In Vitro Validation as New CETP Inhibitors
Volume: 20
Issue: 6
Author(s): Reema Abu Khalaf*, Azhar Shalluf and Maha Habash
Affiliation:
- Department of Pharmacy, Faculty of Pharmacy, Al-Zaytoonah University of Jordan, Amman, Jordan
Keywords:
Cholesteryl ester transfer protein, diaryl sulfonamides, libdock, ligandfit, pharmacophore mapping, hyperlipidemia.
Abstract:
Background: Hyperlipidemia, a cardiovascular disease risk factor, is characterized
by a rise in low-density lipoprotein (LDL), triglycerides and total cholesterol, and a decrease in
high-density lipoprotein (HDL). Cholesteryl ester transfer protein (CETP) enables the transfer
of cholesteryl ester from HDL to LDL and very low-density lipoprotein.
Objectives: CETP inhibition is a promising approach to prevent and treat cardiovascular diseases.
By inhibiting lipid transport activity, it increases HDL levels and decreases LDL levels.
Materials and Method: Herein, diaryl sulfonamides 6a-6g and 7a-7g were prepared, and the
structure of these compounds was fully determined using different spectroscopic techniques.
Results: These compounds underwent biological evaluation in vitro and showed different inhibitory
activities against CETP; 100% inhibitory activity was observed for compounds 7a-7g,
while activities of compounds 6a-6g ranged up to 42.6% at 10 μM concentration. Pharmacophore
mapping agreed with the bioassay results where the four aromatic ring compounds 7a-7g
possessed higher fit values against Hypo4/8 and the shape-complemented Hypo4/8 in comparison
to compounds 6a-6g.
Conclusion: Docking of the synthesized compounds using libdock and ligandfit engines revealed
that compounds 7a-7g formed п-п stacking and hydrophobic interactions with the binding
pocket, while compounds 6a-6g missed these hydrophobic interactions with amino acids
Leu206, Phe265, and Phe263.