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Current Computer-Aided Drug Design

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ISSN (Print): 1573-4099
ISSN (Online): 1875-6697

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Research Article

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

Author(s): Reema Abu Khalaf*, Azhar Shalluf and Maha Habash

Volume 20, Issue 6, 2024

Published on: 18 October, 2023

Page: [987 - 997] Pages: 11

DOI: 10.2174/0115734099268407230927113905

Price: $65

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.

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