1) A series of coumarin-chalcone fibrates were synthesized and evaluated for their PPARα/γ agonist activities and antioxidant properties.
2) Compounds 5a, 5d, and 7a were found to be potent dual PPARα and γ agonists, with compound 5d showing the most potent PPARα agonist activity compared to fenofibrate.
3) Compounds 5d and 6a-6d also exhibited strong antioxidant activities comparable to trolox. Molecular docking studies helped explain the PPARα agonist activity of compound 5d, identifying it as a potential lead compound.
1) A series of coumarin-chalcone fibrates were synthesized and evaluated for their PPARα/γ agonist activities and antioxidant properties.
2) Compounds 5a, 5d, and 7a were found to be potent dual PPARα and γ agonists, with compound 5d showing the most potent PPARα agonist activity compared to fenofibrate.
3) Compounds 5d and 6a-6d also exhibited strong antioxidant activities comparable to trolox. Molecular docking studies helped explain the PPARα agonist activity of compound 5d, identifying it as a potential lead compound.
1) A series of coumarin-chalcone fibrates were synthesized and evaluated for their PPARα/γ agonist activities and antioxidant properties.
2) Compounds 5a, 5d, and 7a were found to be potent dual PPARα and γ agonists, with compound 5d showing the most potent PPARα agonist activity compared to fenofibrate.
3) Compounds 5d and 6a-6d also exhibited strong antioxidant activities comparable to trolox. Molecular docking studies helped explain the PPARα agonist activity of compound 5d, identifying it as a potential lead compound.
1) A series of coumarin-chalcone fibrates were synthesized and evaluated for their PPARα/γ agonist activities and antioxidant properties.
2) Compounds 5a, 5d, and 7a were found to be potent dual PPARα and γ agonists, with compound 5d showing the most potent PPARα agonist activity compared to fenofibrate.
3) Compounds 5d and 6a-6d also exhibited strong antioxidant activities comparable to trolox. Molecular docking studies helped explain the PPARα agonist activity of compound 5d, identifying it as a potential lead compound.
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KIMIA MEDISINAL
Review Jurnal Senyawa Agonis
OLEH SHERLI MELINDA (O1A115068)
KELAS B 1. •Definition of Agonist
2. •Journal’s Review
3. •Conclusion a) Hypertriglyceridemia and hypercholesterolemia are two major factors associated with cardiovascular diseases (CVD), which are the leading cause of mortality worldwide. b) PPARa, one of the three peroxisome proliferator-activated receptor isoforms (a, g, an d b/d), is mainly found in liver, kidney, heart, muscle, and adipose tissue. It plays a cr itical role in fatty acid oxidation and lipoprotein metabolism. PPARa is an important ta rget for the treatment of dyslipidemia. c) PPARg, another very widely investigated PPAR subtype, has been shown to be an impo rtant regulator of target genes involved in glucose and lipid metabolism. d) On the basis of the underlying pathophysiological processes of CVD, therapeutic agen ts possessing both antihyperlipidemic and antioxidant activities are an ideal choice fo r the treatment of CVD and the development of such agents has been the focus of mu ch research in recent years. Fibrates, such as Clofibrate, Fenofibrate and Bezafibrate, have been us ed clinically for many years for the treatment of dyslipidemia to reduce cardiova scular risk. Although it has been demonstrated that fibrates exert their effects by activating PPARa, most of them show weak agonist activities and some of them even display severe adverse effects. Therefore, the development of more effective PPARa agonists is urgent ly needed. Coumarins and chalcones, two types of naturally occurring and synth etic compounds, have attracted enormous research attention because of their di verse biological activities including antioxidant, antihyperglycemic, and antidysli pidemic properties. Fig. 2 Schematic diagram depict ing the procedure for the design of the target compound Ethyl 2-methyl-2-[4-((2-oxo-2H-chromen-3- Ethyl 2-methyl-2-[4-((3-oxo-3H benzo[f]chromen- yl)carbonyl) phenoxy]propanoate (5a). 2-yl) carbonyl)phenoxy]propanoate (5i). Ethyl 2-[4-((6-fluoro-2-oxo-2H-chromen-3- Ethyl 2-methyl-2-[4-((2-oxochroman-3-yl)carbonyl) yl)carbonyl) phenoxy]-2-methylpropanoate (5b). phenoxy]propanoate (6a). Ethyl 2-[4-((6-chloro-2-oxo-2H-chromen-3- Ethyl 2-methyl-2-[4-((6-methyl-2-oxochroman-3- yl)carbonyl) phenoxy]-2-methylpropanoate (5c). yl) carbonyl)phenoxy]propanoate (6b). Ethyl 2-methyl-2-[4-((6-nitro-2-oxo-2H- Ethyl 2-[4-((6,7-dimethoxy-2-oxochroman-3- chromen-3-yl) carbonyl)phenoxy]propanoate (5d). yl)carbonyl) phenoxy]-2-methylpropanoate (6c). Ethyl 2-methyl-2-[4-((6-amino-2-oxo-2H- Ethyl 2-methyl-2-[4-((3-oxo-2,3-dihydro-1H- chromen-3-yl )carbonyl)phenoxy]propanoate (5e). benzo[f]chromene-2-yl) carbonyl)phenoxy]pr- Ethyl 2-methyl-2-[4-((6-methyl-2-oxo-2H- opanoate (6d). chromen-3-yl) carbonyl)phenoxy]propanoate (5f). 2-Methyl-2-[4-((2-oxo-2H-chromen-3- Ethyl2-[4-((6,7-dimethoxy-2-oxo-2H-chromen- yl)carbonyl)phenoxy] propanoic acid (7a). 3-yl)carbonyl)phenoxy]-2-methyl-propanoate 2-Methyl-2-[4-((6-methyl-2-oxo-2H-chromen-3- (5g). yl) carbonyl) phenoxy]propanoic acid (7b). Ethyl 2-[4-((6,8-di-tert-butyl-2-oxo-2H- 2-Methyl-2-[4-((3-oxo-3H-benzo[f]chromene-2- chromen-3-yl)carbonyl)phenoxy]-2- yl)carbonyl) phenoxy]propanoic acid (7c). methylpropan-oate (5h). a. They were subsequently synthesized and evaluated for their PPARa agonist and antioxid ant activities. b. Among these compounds, compounds 5a 5d and 7a were found to possess significant PPARa agonist activities, and compound 5d had the most potent PPARa agonist activity and was 4.3-fold more potent than Fenofibrate. c. In addition, compounds 5a, 5d, and 7a also showed PPARg agonist activities. As a result , compounds 5a, 5d, and 7a were identified as potent PPARa and g dual agonists. d. Furthermore, the antioxidant results revealed that compounds 6a-6d had activity almos t potent than Trolox with IC50 values ranging from 9.40 mM to 17.11 mM, and compou nd 5d also showed good radical scavenging potential (IC50 18.63 mM). e. The significant PPARa agonist activity exhibited by compound 5d was explained by mole cular docking studies. f. Therefore, on the basis of these results, the synthesized coumarin-chalcone fibrates ca n be considered as promising scaffolds for the development of new PPAR agonists, and compound 5d has the potential to be a lead compound for further research. A series of structurally interesting coumarin-chalcone fibrates were synt hesized and evaluated for their PPARa/g agonist activities and antioxidant activiti es. Among these compounds, compounds 5a, 5d, and 7a were identified as poten t PPARa and g dual agonists, and their PPARa agonist activities were found to be more potent than that of Fenofibrate. Furthermore, the results of antioxidant inve stigations revealed that compounds 5d and 6a-6d had activity almost potent tha n Trolox. The agonist activity of PPARa exhibited by compound 5d was examined by molecular docking studies. The results we obtained showed that compound 5 d had the potential to be a lead compound for further research.
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