Irshad Nadeem, Khan Arif-Ullah, Shah Fawad Ali, Nadeem Humaira, Ashraf Zaman, Tipu Muhammad Khalid, Li Shupeng
Riphah Institute of Pharmaceutical Sciences, Riphah International University, Islamabad, Pakistan.
Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan.
Fundam Clin Pharmacol. 2021 Dec;35(6):1119-1132. doi: 10.1111/fcp.12682. Epub 2021 May 2.
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.
高脂血症是动脉粥样硬化迅速发展、心肌梗死和中风中一个值得一提的风险因素。本研究试图确定所选嘧啶衍生物：5-(3-羟基亚苄基)-2,4,6(1H,3H,5H)-嘧啶三酮（SR-5）、5-(4-羟基亚苄基)-2,4,6(1H,3H,5H)-嘧啶三酮（SR-8）、5-(3-氯亚苄基)-2,4,6(1H,3H,5H)-嘧啶三酮（SR-9）和5-(4-氯亚苄基)-2,4,6(1H,3H,5H)-嘧啶三酮（SR-10）对高脂血症的疗效。计算机模拟结果显示，SR-5、SR-8、SR-9和SR-10与3-羟基-3-甲基戊二酰辅酶A（HMGCoA）表现出高亲和力，结合能值分别为-8.2、-8.4、-8.6和-9.5千卡/摩尔，对其他所选靶点的亲和力中等（<-8千卡/摩尔）。体内研究结果表明，受试药物（25和50毫克/千克）显著降低了高脂饮食大鼠的总胆固醇、甘油三酯、低密度脂蛋白、极低密度脂蛋白、动脉粥样硬化指数、冠心病风险指数、碱性磷酸酶、天冬氨酸转氨酶、丙氨酸转氨酶和胆红素，并提高了高密度脂蛋白水平（与高脂饮食组相比，p<0.05，p<0.01，p<0.001）。在动物肝脏组织中，SR-5、SR-8、SR-9和SR-10抑制了HMGCoA还原酶，提高了谷胱甘肽-S-转移酶、还原型谷胱甘肽、过氧化氢酶水平，在组织病理学检查中改善了细胞结构，并降低了炎症标志物的表达：环氧化酶2、肿瘤坏死因子α、磷酸化c-Jun N端激酶和磷酸化核因子κB，这在免疫组织化学和酶联免疫吸附测定分子研究中得到了证实。本研究表明，SR-5、SR-8、SR-9和SR-10具有抗高脂血症作用，可能是通过抑制HMGCoA、肝脏保护、抗氧化和抗炎途径介导的。
