Design, Synthesis, and CETP Inhibitory Evaluation of Novel P-methoxybenzene Sulfonamides Supported by Molecular Modeling
| Author | Reema Abu Khalaf | en |
| Author | Maha Awad | en |
| Author | Mohammad Awad | en |
| Author | Dima Sabbah | en |
| Author | Ghadeer Albadawi | en |
| Orcid | Reema Abu Khalaf [0000-0002-7797-8918] | en |
| Orcid | Maha Awad [0000-0003-0530-6298] | en |
| Orcid | Mohammad Awad [0000-0003-1827-8775] | en |
| Orcid | Dima Sabbah [0000-0003-1428-5097] | en |
| Orcid | Ghadeer Albadawi [0000-0001-8323-8839] | en |
| Issued Date | 2026-12-31 | en |
| 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. | en |
| DOI | https://doi.org/10.5812/ijpr-170876 | en |
| URI | https://brieflands.com/journals/ijpr/articles/170876 | en |
| Keyword | Cholesteryl Ester Transfer Protein | en |
| Keyword | Hyperlipidemia | en |
| Keyword | Induced-fit Docking | en |
| Keyword | Pharmacophore Fingerprint | en |
| Keyword | Sulfonamide Inhibitors | en |
| Publisher | Brieflands | en |
| Title | Design, Synthesis, and CETP Inhibitory Evaluation of Novel P-methoxybenzene Sulfonamides Supported by Molecular Modeling | en |
| Type | Research Article | en |