Molecular Modeling, Cheminformatics Analysis, and Synthesis of Trifluoromethylated Aromatic Sulfonamides as Putative Inhibitors of Cholesteryl Ester Transfer Protein

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.