Design and Synthesis of Linear Acetamides as Cholesterol Lowering Agents

Objective: In the present work, an attempt has been made to mimic Ezetimibe with the design of flexible linear acetamides bearing amino, oxy, and thio groups in beta position as cholesterol absorption inhibitors. Methods: Compounds (I–VII) were prepared and analyzed for cholesterol lowering activity in vivo by determining total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglyceride (TG). Results and Discussion: Among the acetamides prepared, compound (III) (total cholesterol: 137.5; triglycerides: 93.8; HDL: 55.2; LDL: 81; VLDL: 17.8), and compound (VI) (total cholesterol: 134.1; triglycerides: 92.3; HDL: 51.8; LDL: 76.5; VLDL: 17.3) showed excellent in vivo cholesterol lowering activity when compared to all other compounds and even better activity than the standard drug atorvastatin (total cholesterol: 141.7; triglycerides: 95.3; HDL: 57.5; LDL: 83.2; VLDL: 19.5). As a reflection of the cholesterol lowering activities, Wistar albino rats treated with (III) and (VI) showed a maximum decrease in their body weights, 260.4 and 256.3 g respectively, when compared to all other prepared compounds as well as the standard drug (270.7 g). All the synthesized compounds along with the Ezetimibe were docked with the target enzyme Niemann-Pick C1-like1 (NPC1L1) protein (PDB ID: 3QNT), performed by AutoDock 4.0 tool. Conclusions: The molecular docking analysis demonstrated that (III) –4.92 kcal/mol and (VI) –5.36 kcal/mol achieved the highest binding affinity scores with good hydrogen bonds and hydrophobic interactions, all contributed to the stabilization of the compounds at the protein’s target site.