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.