Renoprotective Effects Of Novel Simvastatin Derivatives (A1 And A2) In A Rat Model Of Induced Hypercholesterolemia: Biochemical And Histopathological Evaluation

Abstract

This study explores the synthesis, structural characterization, and evaluation of renal safety of two novel simvastatin ester derivatives (A1 and A2), prepared via a green one-pot esterification method using triphenylohosphine (Ph₃P), iodine (I₂), and 4-dimethylaminopyridine (DMAP). Structural confirmation was achieved using FT-IR, ¹H-NMR, ¹³C-NMR, and mass spectrometry, with key fragmentation patterns supporting successful derivatization. The nephrological safety and potential therapeutic effects of the synthesized compounds were assessed in vivo using a rat model of cholesterol-induced hypercholesterolemia. Biochemical markers of kidney function, including serum creatinine, urea were analyzed alongside detailed histopathological examinations. Treatment with A1 and A2 led to a significant improvement in renal parameters compared to the hypercholesterolemic control group, with A1 showing superior efficacy in reducing urea and BUN levels, while A2 demonstrated better histological preservation of renal architecture. Both derivatives outperformed the reference drug simvastatin in terms of nephrotoxicity mitigation. The findings support the hypothesis that structural modification of simvastatin via esterification with short-chain fatty acids may improve its renal safety profile without compromising its lipid-lowering potential. These results contribute to the growing interest in organ-targeted statin derivatives as safer alternatives in long-term cardiovascular and metabolic disease management.