Design, Synthesis, and CETP Inhibitory Evaluation of Novel P-methoxybenzene Sulfonamides Supported by Molecular Modeling
- 1Faculty of Pharmacy, Al-Zaytoonah University of Jordan Amman Jordan
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.
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BibTeX
@article{khalaf2026design,
title = {{Design, Synthesis, and CETP Inhibitory Evaluation of Novel P-methoxybenzene Sulfonamides Supported by Molecular Modeling}},
author = {Reema Abu Khalaf and Maha Awad and Mohammad Awad and Dima Sabbah and Ghadeer Albadawi},
journal = {Iranian Journal of Pharmaceutical Research : IJPR},
year = {2026},
month = oct,
doi = {10.5812/ijpr-170876},
url = {https://doi.org/10.5812/ijpr-170876},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Design, Synthesis, and CETP Inhibitory Evaluation of Novel P-methoxybenzene Sulfonamides Supported by Molecular Modeling
AU - Reema Abu Khalaf
AU - Maha Awad
AU - Mohammad Awad
AU - Dima Sabbah
AU - Ghadeer Albadawi
PY - 2026
DA - 2026/10/17
JO - Iranian Journal of Pharmaceutical Research : IJPR
DO - 10.5812/ijpr-170876
UR - https://doi.org/10.5812/ijpr-170876
AB - 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.
SN - 1735-0328
SN - 1726-6890
ER -