Thiomethylphenyl Benzenesulfonamides as Potential Cholesteryl Ester Transfer Protein Inhibitors: Synthesis, Molecular Modeling and Biological Evaluation

Background: The number of lipid disorders cases has risen dramatically around the world as a result of poor dietary habits, hereditary risk factors, or other diseases or medicines. Cholesteryl ester transfer protein (CETP) is a 476 amino acid lipophilic glycoprotein that helps transport cholesteryl esters and phospholipids from proatherogenic LDL and VLDL to atheroprotective HDL. CETP inhibition increases HDL cholesterol, lowers LDL cholesterol and triglycerides, rendering it a promising therapy option for hyperlipidemia and its comorbidities. Methods: In this research, fourteen benzenesulfonamides 7a-7g and 8a-8g were synthesized and identified using ¹H-NMR, ¹³C-NMR, IR and MS. The in vitro biological evaluation of 7a- 7g and 8a-8g revealed CETP inhibitory activities ranging from 15.6 to 100% at 10 μM concentration. Results: Four aromatic rings compounds bearing either m-CH3 (8c) or p-Cl (8g) were the most potent compounds with 100% CETP inhibition, while the most active compound was 7c bearing three aromatic rings and m-CH3 with an IC50 of 0.12 μM. LibDock displayed that benzenesulfonamides can form hydrophobic interactions with the side chains of Leu129, Cys13, Ala202, Val198, Leu217 and Ile215 and participate in п-п stacking with Phe441, Phe197 and Arg201 in the binding pocket of CETP. Conclusion: Pharmacophore mapping showed significant matching with the pharmacophoric features of Hypo4/8 and shape-complemented Hypo4/8 of CETP inhibitors for potent compounds.