The class
Chlorinated diaryl sulfonamides identified as potent new CETP inhibitors reaching 100 percent inhibition (Curr Comput Aided Drug Des 2025)
Original title: Chemical Synthesis, Biological Evaluation, and Cheminformatics Analysis of a Group of Chlorinated Diaryl Sulfonamides: Promising Inhibitors of Cholesteryl Ester Transfer Protein
Researchers synthesised ten meta-chlorinated benzene sulfonamide compounds and tested their ability to inhibit cholesteryl ester transfer protein (CETP), an enzyme whose inhibition raises HDL and lowers LDL. In vitro functional CETP assays showed compounds 6e, 6i, and 6j reached 100 percent inhibition, while the remaining seven compounds ranged from 47.5 to 96.5 percent inhibition at 10 micromolar concentration. Pharmacophore mapping and docking studies predicted favourable binding at the CETP active site, with key hydrophobic interactions at His232 and Cys13. The authors found that a chloro group at the ortho position, or a nitro group at the meta or para position, improved CETP inhibitory activity, providing structural guidance for further optimisation of this compound class.
Original abstract
Background: Hyperlipidemia is characterized by an abnormally elevated serum cholesterol, triglycerides, or both. The relationship between an elevated level of LDL and cardiovascular diseases is well-established. Cholesteryl ester transfer protein (CETP) is an enzyme that moves cholesterol esters and triglycerides between LDL, VLDL, and HDL. CETP inhibition leads to a reduction in cardiovascular disease by raising HDL and minimizing LDL.
Objective: This study synthesized ten meta-chlorinated benzene sulfonamides 6a-6j and explored their structure-activity relationship.
Methods: The synthesized molecules were characterized using 1H-NMR, 13C-NMR, IR, and HR-MS. Moreover, cheminformatics analyses included pharmacophore mapping, LibDock studies, and cheminformatics characterization using 2-dimensional (2D) molecular descriptors and principal component analysis.
Results: Based on in vitro functional CETP assays, compounds 6e, 6i, and 6j demonstrated the strongest inhibitory activities against CETP, reaching 100% inhibition. The inhibitory activity of compounds 6a-6d and 6f-6h ranged from 47.5% to 96.5% at 10 μM concentration. Pharmacophore mapping results suggested CETP inhibitory action, while the docking scores and calculated binding energies predicted favoring binding at the CETP active site. Best-scoring docking poses predicted critical hydrophobic features corresponding to key interactions with His232 and Cys13. Cheminformatics analysis using 2D molecular descriptors indicated that the synthesized compounds span various physicochemical properties and drug-likeness.
Conclusion: It was found that a chloro moiety at the ortho-position, or a nitro group at the meta and para-positions, improves the CETP inhibitory activity of synthesized analogs. Computational studies suggest the formation of stable ligand-protein complexes between compounds 6a- 6j and CETP.
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 19 August 2026. Methods.