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Design, Synthesis, and CETP Inhibitory Evaluation of Novel P-methoxybenzene Sulfonamides Supported by Molecular Modeling

Year: 2026

Type: article

Abstract: Background: Hyperlipidemia is a global health concern characterized by elevated blood lipid concentrations, including cholesterol and triglycerides. Cholesteryl ester transfer protein (CETP) plays a crucial role in transferring cholesteryl esters and phospholipids from antiatherogenic high-density lipoproteins to atherogenic low-density and very-low-density lipoproteins. Objectives: This study aimed to synthesize and evaluate 20 p-methoxy-substituted benzene sulfonamides (6a-6j and 7a-7j) as potential CETP inhibitors. Methods: The compounds were synthesized and structurally characterized using infrared (IR) spectroscopy, carbon-13 nuclear magnetic resonance (13C-NMR) spectroscopy, proton nuclear magnetic resonance (1H-NMR) spectroscopy, and high-resolution mass spectrometry, followed by evaluation of CETP inhibitory activity. Molecular modeling studies were also performed. Results: The biological assay showed that inhibitors 7f-7j exhibited the highest inhibitory activity, achieving 100% inhibition at 10 µM; inhibitor 7j had an IC50 of 0.55 µM. Compounds 6a-6j and 7a-7e showed CETP inhibition of up to 95%. The presence of an additional ring markedly enhanced activity, likely due to the hydrophobic nature of CETP. The docking results supported this finding, indicating that ligand/4EWS complex formation was driven by hydrophobic interactions and hydrogen-bond formation with the amino acid residues H232 and R201. Higher binding scores were observed for series 7a-7j than for series 6a-6j, highlighting the importance of introducing an additional ring to enhance CETP inhibition. Furthermore, pharmacophore mapping confirmed that these analogues matched the fingerprint of active CETP inhibitors. Conclusions: A series of novel p-methoxybenzene sulfonamides was synthesized and evaluated as CETP inhibitors.

Source: Iranian journal of pharmaceutical research

DOI: 10.5812/ijpr-170876

Authors: Reema Abu Khalaf, Maha Awad, Mohammad Awad, Dima Sabbah, Ghadeer Albadawi

Institution: Al-Zaytoonah University of Jordan

Language: English

Topic: Heterocyclic Compound Synthesis and Bioactivity

Subfield: Organic Chemistry

Field: Chemistry

Domain: Physical Sciences

SDG: Good health and well-being

Open Access status: hybrid

Funder: Al-Zaytoonah University of Jordan