Pharmacology
Newly synthesised fluorinated diaryl sulfonamides reach 100% CETP inhibition in vitro, guided by molecular modelling (Curr Comput Aided Drug Des 2024)
Original title: Fluorinated Diaryl Sulfonamides: Molecular Modeling, Synthesis, and In Vitro Validation as New CETP Inhibitors
A medicinal chemistry study synthesised two series of diaryl sulfonamides, 6a-6g and 7a-7g, as candidate CETP inhibitors, confirming their structures spectroscopically. In vitro biological evaluation found the four-aromatic-ring series 7a-7g reached 100% CETP inhibitory activity, while the 6a-6g series reached up to 42.6% at 10 uM. Pharmacophore mapping showed the 7a-7g compounds fit the model shape better than 6a-6g, and docking using libdock and ligandfit engines showed the 7a-7g compounds formed pi-pi stacking and hydrophobic interactions within the CETP binding pocket that the 6a-6g compounds lacked, including contacts with residues Leu206, Phe265 and Phe263. Early-stage medicinal chemistry with in vitro enzyme inhibition data only, no cell, animal or human testing.
Original 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.
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.