Synthesis, Molecular Modeling, and Evaluation of Novel Methylated Benzene Sulfonamide Derivatives as Cholesteryl Ester Transfer Protein (CETP) Inhibitors

Cardiovascular disease (CVD) is a leading cause of global mortality, with dyslipidemia being a significant modifiable risk factor. Dyslipidemia refers to all abnormalities in blood lipid levels. It plays a fundamental role in the development and progression of atherosclerosis. The reduction of low-density lipoprotein (LDL) cholesterol has been shown to decrease cardiovascular risk. Cholesteryl ester transfer protein (CETP) plays a role in LDL metabolism, and its inhibition results in lower LDL levels. This study synthesizes and evaluates novel benzene sulfonamide derivatives as CETP inhibitors. Twenty compounds were synthesized and tested for their inhibitory activity using an in vitro bioassay. The results revealed that para-methylated derivatives exhibited higher inhibitory activity compared to meta-methylated derivatives, where compound 6n has an IC50 of 24.4 mu M. Furthermore, electron withdrawing groups such as chlorine and nitro substitutions on the sulfanamido-phenyl rings demonstrated superior inhibitory effects compared to electron donating groups. Positional isomerism of the substitutions also influenced inhibitory activity, with para substitutions being more effective. Nitro-substituted compounds showed greater inhibition than chlorine-substituted compounds, where compound 6t has an IC50 of 18.3 mu M. Overall, this study provides valuable insights into the SAR of CETP inhibitors and identifies promising compounds for further investigation as potential therapeutics for CVD.