Synthesis of New Atorvastatin Derivatives and Assessing Their Effect on Liver and Kidney Serum Parameters, Function, and Histology in Rabbits

Abstract

Background and Objectives: Cardiovascular diseases are the main 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, as the inhibitors of HMG-CoA reductase, are often used as cholesterol-lowering drugs to prevent cardiovascular diseases. This study aims to synthesize novel derivatives of atorvastatin and investigate their effect on liver and kidney serum parameters, function, and histology. Methods: Atorvastatin derivatives named S1, S2, and S3 were synthesized by acylation of the benzene ring of atorvastatin. The effect of compound S3 on serum parameters related to liver and kidney function was evaluated in rabbits with a high-fat diet-induced hypercholesterolemia. SPSS software, version 20 was used to analyze the data using statistical tests. Results: The compound S3 increased high-density lipoprotein cholesterol and reduced total cholesterol, low-density lipoprotein, and triglyceride compared to the standard drug atorvastatin during 30 days of treatment (P<0.05). The liver enzymes were used to evaluate the toxicity of compound S3. In addition, the S3 compound significantly reduced the amount of urea, creatinine, and uric acid compared to the hyperlipidemic group. Histological study results showed that the compound S3 reduces tissue damage in hypercholesterolemic rabbits. Conclusion: The S3 compound of atorvastatin can be considered as a cholesterol-lowering agent. This indicates that phenyl rings with higher electron density attached to propargyl show better inhibitory effects against ?? The S3 can be an effective drug for preventing atherosclerosis. However, more research is needed to clarify its exact mechanism.

Keywords

• atorvastatin
• synthesis
• blood cholesterol
• hmg-coa reductase