Synthesis, Docking and Evaluation of Phenylacetic Acid and Trifluoro-methylphenyl Substituted Benzamide Derivatives as Potential PPARδ Agonists

Background: Peroxisome proliferator-activated receptor (PPAR) δ is a type of PPARs belonging to the steroid or nuclear hormone receptor super family. Activation of PPARδ leads to metabolism of fat instead of glucose by body for energy requirements. PPARδ represent an emerging pharmacological target for the treatment of metabolic syndrome (MS). Many selective and potent PPARδ 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 PPARδ 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 PPARδ 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 PPARδ agonists for the potential treatment of MS and related diseases.