Design,synthesis and evaluation of 5-(4-hydroxyphenyl)-3H-1,2-dithiole-3-thione-Based fibrates as potential hypolipidemic and hepatoprotective agents |
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| Affiliation: | 1. College of Pharmacy, Xi’an Jiaotong University, No. 76 Yanta West Road, Xi’an, Shaanxi Province 710061, People’s Republic of China;2. College of Pharmacy, Shaanxi University of Chinese Medicine, Shiji Ave., Xi’an-xianyang New Economic Zone, Xi’an, Shaanxi Province 710061, People’s Republic of China;1. Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, and School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, PR China;2. Wuya College of Innovation, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, PR China;3. Department of Medicinal Chemistry and State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjia Xiang, Nanjing 210009, PR China;4. Jiangsu Kanion Pharmaceutical Co., Ltd., 58 Kangyuan Road, Lianyungang 222001, PR China;1. Postovsky Institute of Organic Synthesis, Ural Branch of Russian Academy of Sciences, Ekaterinburg 620990, Russia;2. Institute of Physiologically Active Compounds, Russian Academy of Sciences, Chernogolovka 142432, Russia;3. Ural Federal University Named After the First President of Russia B.N. Yeltsin, Ekaterinburg 620002, Russia;4. Emanuel Institute of Biochemical Physics Russian Academy of Sciences, Moscow 119334, Russia;5. Departments of Environmental Health Sciences and Neurology, University of Michigan, Ann Arbor, MI 48109, USA;6. Center for Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA;1. State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, PR China;2. Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, Nanjing 210009, PR China;1. School of Pharmacy, Second Military Medical University, Shanghai 200433, China;2. Department of Chemistry, Fudan University, Shanghai 200433, China;3. State Key Lab of New Drug and Pharmaceutical Process, Shanghai Institute of Pharmaceutical Industry, Shanghai 200040, China;4. Fujian Provincial Key Laboratory of Medical Analysis, Fujian Academy of Medical Sciences, Fuzhou 350001, China;1. Department of Biochemistry and Structural Biology, University of Texas Health at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX, 78229, USA;2. Department of Internal Medicine, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC, 27157, USA;3. Department of Pathology, University of Texas Health at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX, 78229, USA |
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| Abstract: | Six novel target compounds 5-(4-hydroxyphenyl)-3H-1,2-dithiole-3-thione (ADT) based fibrates were synthesized and evaluated. All the synthesized compounds were preliminarily screened by using the Triton WR-1339-induecd hyperlipidemia model, in which T1 exhibited more potent hypolipidemic property than positive drug fenofibrate (FF). T1 also significantly decreased serum triglycerides (TG), total cholesterol (TC) and low density lipoprotein cholesterin (LDL) in methionine solution (Mets) induced hyperlipidemic mice. Moreover, hepatic transaminases (AST and ALT) were obviously ameliorated after treatment with T1 and the histological observation indicated that T1 ameliorated the injury in liver tissue and inhibited the hepatic lipid accumulation. In the livers of T1-administrated rat, the levels of PPARα related to lipids metabolism were up-regulated. Additional effects such as antioxidant, anti-inflammatory and H2S releasing action confirmed and reinforced the activity of T1 as a potential multifunctional hypolipidemic and hepatoprotective agent. |
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| Keywords: | Fibrates analogs Lipid-lowering Hepatoprotection |
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