Antihyperlipidemic effect of selected pyrimidine derivatives mediated through multiple pathways

Abstract

Hyperlipidemia is worth-mentioning risk factor in quickly expanding atherosclerosis, myocardial infarction, and stroke. This study attempted to determine effectiveness of selected pyrimidine derivatives: 5-(3-Hydroxybenzylidene)-2, 4, 6(1H, 3H, 5H)-pyrimidinetrione (SR-5), 5-(4-Hydroxybenzylidene)-2, 4, 6(1H, 3H, 5H)-pyrimidinetrione (SR-8), 5-(3-Chlorobenzylidene)-2, 4, 6(1H, 3H, 5H)-pyrimidinetrione (SR-9), and 5-(4-Chlorobenzylidene)-2, 4, 6(1H, 3H, 5H)-pyrimidinetrione (SR-10) against hyperlipidemia. In silico results revealed that SR-5, SR-8, SR-9, and SR-10 exhibited high affinity with 3-hydroxy-3-methylglutaryl coenzyme A (HMGCoA) possessing binding energy values of -8.2, -8.4, -8.6, and -9.5 Kcal/mol, respectively, and moderate (<-8 Kcal/mol) against other selected targets. In vivo findings showed that test drugs (25 and 50 mg/Kg) significantly decreased HFD rat total cholesterol, triglycerides, low-density lipoprotein, very-low-density lipoprotein, atherogenic index, coronary risk index, alkaline phosphatase, aspartate transaminase, alanine transaminase, and bilirubin and increased high-density lipoprotein (p < 0.05, p < 0.01, p < 0.001 vs HFD group). In animal liver tissues, SR-5, SR-8, SR-9, and SR-10 inhibited HMGCoA reductase enzyme, enhanced glutathione-s-transferase, reduced glutathione, catalase levels, improved cellular architecture in histopathological examination, and decreased expression of inflammatory markers: cyclo-oxygenase 2, tumor necrosis factor alpha, phosphorylated c-Jun N-terminal kinase, and phosphorylated-nuclear factor kappa B, evidenced in immunohistochemistry and enzyme-linked immunosorbent assay molecular investigations. This study indicates that SR-5, SR-8, SR-9, and SR-10 exhibit antihyperlipidemic action, mediated possibly through HMGCoA inhibition, hepatoprotection, antioxidant, and anti-inflammatory pathways.

Keywords: anti-inflammatory; antihyperlipidemic; antioxidant; computational pharmacology; hepatoprotective; pyrimidines.