Design, synthesis and evaluation of 5-(4-hydroxyphenyl)-3H-1,2-dithiole-3-thione-Based fibrates as potential hypolipidemic and hepatoprotective agents.

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.

Development of Fibrates as Important Scaffolds in Medicinal Chemistry.

Fibrates are a class of phenoxyisobutyric acid derivatives mainly used as anti-hyperlipidemic agents. The fibrate scaffold has undergone a variety of chemical modifications, providing a wide spectrum of biological activities. Within the last few years, the majority of new synthetic fibrate derivatives have demonstrated hypolipidemic activity through peroxisome proliferator-activated receptor α (PPARα) activation. However, some compounds containing the fibrate scaffold have shown different pharmacological properties, also independent of PPARα activation, such as anti-inflammatory, analgesic, antioxidant, and antiplatelet activities. The aim of this review is to highlight the structure-activity relationships (SAR) in evaluating the significance of fibrates in the field of medicinal chemistry.

A novel structural class of coumarin-chalcone fibrates as PPARα/γ agonists with potent antioxidant activities: Design, synthesis, biological evaluation and molecular docking studies.

A series of structurally interesting coumarin-chalcone fibrates were synthesized and evaluated for their PPARα/γ agonist activities and antioxidant activities. Among these compounds, compounds 5a, 5d, and 7a were identified as potent PPARα and γ dual agonists, and their PPARα agonist activities were found to be more potent than that of Fenofibrate. Furthermore, the results of antioxidant investigations revealed that compounds 5d and 6a-6d had greater potency than Trolox with IC50 values ranging from 9.40 µM to 18.63 µM. The structure-activity relationship revealed that the electron-withdrawing nitro group substituted at the C6' position of the benzopyran moiety increased the PPARα and γ agonist efficacy. Moreover, the presence of a double bond on the benzopyran moiety was essential for PPARα and γ agonist efficacy. The agonist activity of PPARα exhibited by compound 5d was examined by molecular docking studies. Taken together, the results we obtained showed that compound 5d had the potential to be a lead compound for further research.

Discovery of amide based fibrates as possible antidyslipidemic and antioxidant agents.

A novel series of amide based fibrates were synthesized and evaluated for antidyslipidemic activity in triton induced hyperlipidemic rats. Interestingly, the compound 13 produced striking reduction in serum levels of total cholesterol (TC), phospholipids (PL) and triglycerides (TG). In addition, it exhibited improved lipoprotein lipase activity and found to possess moderate radical scavenging potential. The results of the above studies shows that the compounds synthesized on fibrate based pharmacophores might result in identification of new lead for dyslipidemia.

Indole-based fibrates as potential hypolipidemic and antiobesity agents.

Hypolipidemic and antiobesity effects of the newly synthesized indole-based fibrates were evaluated in Triton WR-1339 and high fat diet (HFD)-induced hyperlipidemic rats. Preliminary screening of all the synthesized compounds was done by using an acute model (Triton model), in which compounds 3f and 3l showed significant antidyslipidemic activity. Furthermore, these compounds 3f and 3l were found to induce significant weight loss in the visceral fat mass of HFD-fed hyperlipidemic rats without affecting the normal feeding behavior. Histological examination of the liver of rats supplemented with 3f and 3l revealed a significant decrease in steatosis when compared to the effect of the standard drug fenofibrate. Additional effects such as an increase in lecithin cholesterol acyl-transferase (LCAT) enzyme level and increased receptor mediated catabolism of I(131)-low density lipoproteins (LDL) confirm and reinforce the efficacy of both of these compounds as a new class of dual-acting hypolipidemic and antiobesity agents.

Microwave-assisted synthesis, hypolipidemic and hypoglycemic activity of some novel 2-(4-(2-Amino-6-(4-substituted phenyl)-pyrimidin-4-yl)-phenoxy)-2-methyl propanoic acid derivatives.

A novel series of aminopyrimidines containing the phenoxy isobutyric acid group as a pharmacophore was synthesized using conventional and microwave assisted methods of synthesis. The compounds were synthesized in good yields (70-89%) by the microwave-assisted one-pot protocol in much shorter reaction times. The synthesized compounds were evaluated for their hypolipidemic and hypoglycemic activity by high-fat diet-induced hyperlipidemia and hyperglycemia in male Sprague-Dawley rats. The present investigation showed significant antihyperlipidemic and antihyperglycemic activity for all compounds of the series when compared with the standard drug. Structure-activity relationship (SAR) for the series were developed by comparing total lipid profile data of synthesized compounds with fenofibrate as standard drug.

Synthesis and antidyslipidemic activity of chalcone fibrates.

A series of chalcone based PPAR-α agonists were synthesized and evaluated for their antidyslipidemic activity in high fructose high fat fed dyslipidemic Syrian golden hamsters. Most of the compounds exhibited antidyslipidemic activity. The compounds 4c and 4f have been identified as most potent antidyslipidemics. A definite structure-activity relationship was observed while varying the nature as well as the position of the substituent.

Structural insight into the crucial role of ligand chirality in the activation of PPARs by crystallographic methods.

Peroxisome Proliferator-Activated Receptors (PPARs) are ligand-activated transcription factors that govern lipid and glucose homeostasis playing a central role in cardiovascular disease, obesity, and diabetes. These receptors show a high degree of stereoselectivity towards several classes of drugs. This review provides an overview of most papers reporting the influence of stereochemistry on PPAR activation. Some cases in which chirality is a crucial point in determining the PPAR binding mode are reviewed and discussed with the aim to show how enantiomeric recognition originates at the molecular level. The structural characterization by crystallographic methods of complexes formed by PPARs with their ligands turns out to be an essential tool to explain receptor stereoselectivity.

Synthesis, hypolipidemic and hypoglycemic activity of some novel 2-(4-(2-substituted aminothiazole-4-yl) phenoxy)-2-methyl propanoic acid derivatives.

An improved synthetic protocol for a novel series of 2-(4-(2-substituted aminothiazole-4-yl) phenoxy)-2-methyl propanoic acid derivatives has been developed using different methods of synthesis. The synthesized compounds are evaluated for their hypolipidemic and hypoglycemic activity by high fat diet induced hyperlipidemia and hyperglycemia in Sprague-Dawley rats.