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This study attempted to determine effectiveness of selected pyrimidine derivatives: 5\u2010(3\u2010Hydroxybenzylidene)\u20102, 4, 6(<jats:italic>1H<\/jats:italic>, <jats:italic>3H<\/jats:italic>, <jats:italic>5H<\/jats:italic>)\u2010pyrimidinetrione (SR\u20105), 5\u2010(4\u2010Hydroxybenzylidene)\u20102, 4, 6(<jats:italic>1H<\/jats:italic>, <jats:italic>3H<\/jats:italic>, <jats:italic>5H<\/jats:italic>)\u2010pyrimidinetrione (SR\u20108), 5\u2010(3\u2010Chlorobenzylidene)\u20102, 4, 6(<jats:italic>1H<\/jats:italic>, <jats:italic>3H<\/jats:italic>, <jats:italic>5H<\/jats:italic>)\u2010pyrimidinetrione (SR\u20109), and 5\u2010(4\u2010Chlorobenzylidene)\u20102, 4, 6(<jats:italic>1H<\/jats:italic>, <jats:italic>3H<\/jats:italic>, <jats:italic>5H<\/jats:italic>)\u2010pyrimidinetrione (SR\u201010) against hyperlipidemia. <jats:italic>In<\/jats:italic> <jats:italic>silico<\/jats:italic> results revealed that SR\u20105, SR\u20108, SR\u20109, and SR\u201010 exhibited high affinity with 3\u2010hydroxy\u20103\u2010methylglutaryl coenzyme A (HMGCoA) possessing binding energy values of \u22128.2, \u22128.4, \u22128.6, and \u22129.5\u00a0Kcal\/mol, respectively, and moderate (&lt;\u22128\u00a0Kcal\/mol) against other selected targets. <jats:italic>In<\/jats:italic> <jats:italic>vivo<\/jats:italic> findings showed that test drugs (25 and 50\u00a0mg\/Kg) significantly decreased HFD rat total cholesterol, triglycerides, low\u2010density lipoprotein, very\u2010low\u2010density lipoprotein, atherogenic index, coronary risk index, alkaline phosphatase, aspartate transaminase, alanine transaminase, and bilirubin and increased high\u2010density lipoprotein (<jats:italic>p<\/jats:italic>\u00a0&lt;\u00a00.05, <jats:italic>p<\/jats:italic>\u00a0&lt;\u00a00.01, <jats:italic>p<\/jats:italic>\u00a0&lt;\u00a00.001 vs HFD group). In animal liver tissues, SR\u20105, SR\u20108, SR\u20109, and SR\u201010 inhibited HMGCoA reductase enzyme, enhanced glutathione\u2010s\u2010transferase, reduced glutathione, catalase levels, improved cellular architecture in histopathological examination, and decreased expression of inflammatory markers: cyclo\u2010oxygenase 2, tumor necrosis factor alpha, phosphorylated c\u2010Jun N\u2010terminal kinase, and phosphorylated\u2010nuclear factor kappa B, evidenced in immunohistochemistry and enzyme\u2010linked immunosorbent assay molecular investigations. This study indicates that SR\u20105, SR\u20108, SR\u20109, and SR\u201010 exhibit antihyperlipidemic action, mediated possibly through HMGCoA inhibition, hepatoprotection, antioxidant, and anti\u2010inflammatory pathways.<\/jats:p>","DOI":"10.1111\/fcp.12682","type":"journal-article","created":{"date-parts":[[2021,4,20]],"date-time":"2021-04-20T00:47:58Z","timestamp":1618879678000},"page":"1119-1132","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Antihyperlipidemic effect of selected pyrimidine derivatives mediated through multiple pathways"],"prefix":"10.1111","volume":"35","author":[{"given":"Nadeem","family":"Irshad","sequence":"first","affiliation":[{"name":"Riphah Institute of Pharmaceutical Sciences Riphah International University  Islamabad Pakistan"},{"name":"Department of Pharmacy Faculty of Biological Sciences Quaid\u2010i\u2010Azam University  Islamabad 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