Design, synthesis, and biological evaluation of novel atorvastatin derivatives

Abstract

Cardiovascular disease is the leading cause of death worldwide. High cholesterol level is a risk factor for coronary artery disease. Cholesterol production is regulated by the enzyme 3‑hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. Statins, HMG-CoA reductase inhibitors, are often used as lipid-lowering drugs to prevent cardiovascular disease. Therefore, this study aimed to evaluate the inhibitory activity of several atorvastatin derivatives and assess their inhibitory activity against the HMG-CoA reductase enzyme. Atorvastatin derivatives S1, S2, and S3 were synthesized by acylation of the benzene ring of atorvastatin. Moreover, the amine group of atorvastatin was treated with ethanol and sulfuric acid, to provide atorvastatin-anthranilic acid derivatives (S4 and S5). An in silico docking study was performed on the HMG-CoA reductase (PDB ID: 1HWK), and it was observed that compound S3 with a propargyl functional group had the highest binding affinity (∆G= -6.8 kcal/mol). The obtained results showed that S3 compound could significantly inhibit HMG-CoA reductase activity compared to controls pravastatin and atorvastatin (P<0.05). The in vivo antihyperlipidemic activity results discovered that compound S3 increased HDL, and decreased cholesterol, LDL and triglyceride compared to the atorvastatin during 60 days of treatment (P < 0.05). Liver enzyme levels and rabbit liver histology study showed no toxicity for the S3 compound. Additionally, the S3 might be considered as an effective medicine in preventing atherosclerosis.