Pharmacology
Trifluoromethylated sulfonamides reach 100% CETP inhibition in vitro, guided by induced fit docking and pharmacophore mapping (Med Chem 2023)
Original title: Trifluoromethylated Aryl Sulfonamides as Novel CETP Inhibitors: Synthesis, Induced Fit Docking, Pharmacophore Mapping and Subsequent In vitro Validation
A medicinal chemistry study prepared fourteen trifluoromethyl-substituted benzene sulfonamides (series 6a-6g and 7a-7g) as candidate CETP inhibitors, characterised by NMR, IR and high-resolution mass spectrometry. In vitro biological evaluation found compounds 7d-7f reached 100% CETP inhibition, while the rest of the series ranged from 2% to 72% inhibition at 10 uM. Adding a fourth aromatic ring markedly improved activity, attributed to the hydrophobic nature of the CETP binding pocket, and ortho-chloro, meta-chloro and para-methyl substituents also boosted potency. Induced fit docking showed hydrophobic interactions plus hydrogen bonding with residues Q199, R201 and H232 guided binding, and pharmacophore mapping showed the series matches the functional profile of existing CETP inhibitors. Early-stage medicinal chemistry with in vitro enzyme data only.
Original abstract
Background: Cardiovascular disease is one of the leading causes of death. Atherosclerosis causes arterial constriction or obstruction, resulting in acute cardiovascular illness. Cholesteryl ester transfer protein (CETP) facilitates reverse cholesterol transport. It supports the transfer of cholesteryl ester from HDL to LDL and VLDL. Inhibition of CETP by drugs limits cardiovascular disease by decreasing LDL and increasing HDL.
Objectives: In this study, fourteen trifluoromethyl substituted benzene sulfonamides 6a-6g and 7a-7g were prepared.
Methods: The synthesized molecules were characterized using 1H-NMR, 13C-NMR, IR and HR-MS. They were in vitro tested to estimate their CETP inhibitory activity.
Results: In vitro biological evaluation showed that compounds 7d-7f had the highest inhibitory activity with 100% inhibition, while the inhibition observed by compounds 6a-6g, 7a-7c and 7g ranged from 2%-72% at 10 μM concentration. It was found that the addition of a fourth aromatic ring significantly improved the activity, which may be due to the hydrophobic nature of CETP. Also, the presence of ortho-chloro, meta-chloro and para-methyl substituents results in high inhibitory activity.
Conclusion: The induced fit docking studies revealed that hydrophobic interaction guided ligand/ CETP binding interaction in addition to H-bond formation with Q199, R201, and H232. Furthermore, pharmacophore mapping demonstrated that this series satisfies the functionalities of the current CETP inhibitors.
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.