A Series of Ferulic Acid Amides Reveals Unexpected Peroxiredoxin 1 Inhibitory Activity with in vivo Antidiabetic and Hypolipidemic Effects

Published in: Journal, Article, Research Support, Non-U.S. Gov’t Volume : 16, Issue : 3, Pages : 484-498

DOI : 10.1002/cmdc.202000564

Author : Yasmin, Sabina; Cerchia, Carmen; Badavath, Vishnu Nayak; Laghezza, Antonio; Dal Piaz, Fabrizio; Mondal, Susanta K.; Atli, Oezlem; Baysal, Merve; Vadivelan, Sankaran; Shankar, S.; Siddique, Mohd. Usman Mohd.; Pattnaik, Ashok Kumar; Singh, Ravi Pratap; Loiodice, Fulvio; Jayaprakash, Venkatesan; Lavecchia, Antonio

Abstract : Insulin resistance is a major pathophysiol. 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 mol. 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 (I) and (II) bound PRDX1 and induced a dose-dependent inhibition. Furthermore, I and II significantly improved hyperglycemia and hyperlipidemia in streptozotocin-nicotinamide (STZ-NA)-induced diabetic rats as confirmed by histopathol. examinations These results provide guidance for developing the current FAAs as new potential antidiabetic agents.