Molecular Modeling, Cheminformatics Analysis, and Synthesis of Trifluoromethylated Aromatic Sulfonamides as Putative Inhibitors of Cholesteryl Ester Transfer Protein
Reema Abu Khalaf, Rawan Hamadah, Nataly Abu Ajamieh, Rima Hajjo, Mahmoud A. Al-Sha’er, Dima A. Sabbah · ChemistrySelect · 2025
Abstract Elevated lipid profile is a major risk factor for diseases like dyslipidemia. Cholesteryl ester transfer protein (CETP) inhibitors are explored for their potential to raise HDL and lower LDL, offering a promising approach to reducing cardiovascular risk. In this study, a series of ortho ‐ and meta ‐trifluoromethylated sulfonamides 6a‐6t were synthesized and evaluated for their CETP inhibitory activity at 10 µM concentration. Compounds 6a‐6t featured various aromatic substituents, positioned at different sites. Results revealed that compound 6f demonstrated the highest inhibitory efficacy, achieving a 100% inhibition. CETP inhibition was compared to computational models Hypo‐1 and Hypo‐1‐shaped to predict potential biological efficacy. The findings indicate that electron‐withdrawing groups, particularly Cl and NO₂, significantly enhance CETP inhibitory potency, especially when located at the ortho or meta positions. These compounds exhibited a strong correlation between Hypo‐1 activity and % inhibition, suggesting improved interaction with CETP. In contrast, methyl electron‐donating substitutions resulted in lower activity, indicating their inadequacy for this scaffold. Further cheminformatics analyses based on molecular descriptors indicated that 6f has enhanced lead‐like and drug‐like properties in comparison to the second most potent compound 6i (82%). Developing new compounds with CETP inhibitory properties shows promise for future interventions to regulate lipid profiles.