1. A Series of Ferulic Acid Amides Reveals Unexpected Peroxiredoxin 1 Inhibitory Activity with in vivo Antidiabetic and Hypolipidemic Effects
- Author
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Özlem Atlı, Sabina Yasmin, Antonio Lavecchia, Susanta Kumar Mondal, Fulvio Loiodice, S K Shankar, Merve Baysal, Mohd Usman Mohd Siddique, Fabrizio Dal Piaz, Ravi Pratap Singh, Venkatesan Jayaprakash, Carmen Cerchia, Sankaran Vadivelan, Ashok Kumar Pattnaik, Antonio Laghezza, Vishnu Nayak Badavath, Yasmin, S., Cerchia, C., Badavath, V. N., Laghezza, A., Dal Piaz, F., Mondal, S. K., Atli, O., Baysal, M., Vadivelan, S., Shankar, S., Siddique, M. U. M., Pattnaik, A. K., Singh, R. P., Loiodice, F., Jayaprakash, V., and Lavecchia, A.
- Subjects
Male ,Models, Molecular ,Antioxidant ,endocrine system diseases ,medicine.medical_treatment ,Peroxisome proliferator-activated receptor ,Pharmacology ,01 natural sciences ,Biochemistry ,Peroxiredoxin 1 ,Rats, Sprague-Dawley ,Ferulic acid ,Transactivation ,chemistry.chemical_compound ,Ferulic acid amide ,Drug Discovery ,Tumor Cells, Cultured ,Enzyme Inhibitors ,General Pharmacology, Toxicology and Pharmaceutics ,Hypolipidemic Agents ,chemistry.chemical_classification ,Molecular Structure ,Type 2 diabetes ,Hyperlipidemia ,Molecular Medicine ,Ferulic acid amides ,Coumaric Acids ,Cell Survival ,Streptozocin ,Diabetes Mellitus, Experimental ,Structure-Activity Relationship ,Insulin resistance ,Picrates ,In vivo ,medicine ,Animals ,Humans ,Hypoglycemic Agents ,Rats, Wistar ,Dose-Response Relationship, Drug ,010405 organic chemistry ,Biphenyl Compounds ,Organic Chemistry ,Peroxiredoxins ,medicine.disease ,Amides ,Hypoglycemia ,Rats ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,chemistry ,Docking (molecular) ,Hyperglycemia - Abstract
Insulin resistance is a major pathophysiological feature in the development of type 2 diabetes (T2DM). Ferulic acid is known for attenuating the insulin resistance and reducing the blood glucose in T2DM rats. In this work, we designed and synthesized a library of new ferulic acid amides (FAA), which could be considered as ring opening derivatives of the antidiabetic PPARγ agonists Thiazolidinediones (TZDs). However, since these compounds displayed weak PPAR transactivation capacity, we employed a proteomics approach to unravel their molecular target(s) and identified the peroxiredoxin 1 (PRDX1) as a direct binding target of FAAs. Interestingly, PRDX1, a protein with antioxidant and chaperone activity, has been implied in the development of T2DM by inducing hepatic insulin resistance. SPR, mass spectrometry-based studies, docking experiments and in vitro inhibition assay confirmed that compounds VIe and VIf bound PRDX1 and induced a dose-dependent inhibition. Furthermore, VIe and VIf significantly improved hyperglycemia and hyperlipidemia in streptozotocin-nicotinamide (STZ-NA)-induced diabetic rats as confirmed by histopathological examinations. These results provide guidance for developing the current FAAs as new potential antidiabetic agents.
- Published
- 2020