147410-78-4Relevant articles and documents
Synthesis,docking and evaluation of phenylacetic acid and trifluoro-methylphenyl substituted benzamide derivatives as potential ppar? agonists
Grewal, Ajmer Singh,Lather, Viney,Pandita, Deepti,Bhayana, Garima
, p. 1239 - 1251 (2017/11/14)
Background: Peroxisome proliferator-activated receptor (PPAR) ? is a type of PPARs belonging to the steroid or nuclear hormone receptor super family. Activation of PPAR? leads to metabolism of fat instead of glucose by body for energy requirements. PPAR? represent an emerging pharmacological target for the treatment of metabolic syndrome (MS). Many selective and potent PPAR? agonists had been synthesized with a potential role in the treatment of various disorders associated with MS including type 2 diabetes and inflammation. Objective: The present work was designed to synthesize and evaluate the antidiabetic and anti-inflammatory activity of some newer phenylacetic acid and trifluoromethylphenyl substituted benzamide derivatives as potential PPAR? agonists. Methods: This work involved the synthesis of newer sulfamoyl benzamide derivatives and their evaluation by molecular docking studies to determine the binding interactions for the best fit conformations in the binding site of the PPAR? protein. Based on the results of the in silico studies, the selected compounds were tested for their antidiabetic and anti-inflammatory activity in the animal models. Results: Amongst the synthesized molecules, compound 7 showed higher anti-diabetic activity and compound 19 showed higher anti-inflammatory activity. The experimental results were found to be in concordance with that of the in silico results. Most of the synthesized molecules were found to have drug like properties as devised by Lipinski's rule of five. Conclusion: These molecules can act as the starting hits for the design of safe, effective and bioavailable PPAR? agonists for the potential treatment of MS and related diseases.
Development and characterization of 3-(benzylsulfonamido)benzamides as potent and selective SIRT2 inhibitors
Khanfar, Mohammad A.,Quinti, Luisa,Wang, Hua,Choi, Soo Hyuk,Kazantsev, Aleksey G.,Silverman, Richard B.
, p. 414 - 426 (2014/03/21)
Inhibitors of sirtuin-2 deacetylase (SIRT2) have been shown to be protective in various models of Huntington's disease (HD) by decreasing polyglutamine aggregation, a hallmark of HD pathology. The present study was directed at optimizing the potency of SIRT2 inhibitors containing the neuroprotective sulfobenzoic acid scaffold and improving their pharmacology. To achieve that goal, 176 analogues were designed, synthesized, and tested in deacetylation assays against the activities of major human sirtuins SIRT1-3. This screen yielded 15 compounds with enhanced potency for SIRT2 inhibition and 11 compounds having SIRT2 inhibition equal to reference compound AK-1. The newly synthesized compounds also demonstrated higher SIRT2 selectivity over SIRT1 and SIRT3. These candidates were subjected to a dose-response bioactivity assay, measuring an increase in α-tubulin K40 acetylation in two neuronal cell lines, which yielded five compounds bioactive in both cell lines and eight compounds bioactive in at least one of the cell lines tested. These bioactive compounds were subsequently tested in a tertiary polyglutamine aggregation assay, which identified five inhibitors. ADME properties of the bioactive SIRT2 inhibitors were assessed, which revealed a significant improvement of the pharmacological properties of the new entities, reaching closer to the goal of a clinically-viable candidate.
