Fluorinated Diaryl Sulfonamides: Molecular Modeling, Synthesis, and In Vitro Validation as New CETP Inhibitors

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.

Objective: 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.

Cite this article as:

Khalaf Abu Reema*, Shalluf Azhar and Habash Maha, Fluorinated Diaryl Sulfonamides: Molecular Modeling, Synthesis, and In Vitro Validation as New CETP Inhibitors, Current Computer-Aided Drug Design 2024; 20 (6) . https://dx.doi.org/10.2174/0115734099268407230927113905