In Search for Multi-Target Ligands as Potential Agents for Diabetes Mellitus and Its Complications—A Structure-Activity Relationship Study on Inhibitors of Aldose Reductase and Protein Tyrosine Phosphatase 1B

Abstract

Diabetes mellitus (DM) is a complex disease which currently affects more than 460 million people and is one of the leading cause of death worldwide. Its development implies numerous metabolic dysfunctions and the onset of hyperglycaemia-induced chronic complications. Multiple ligands can be rationally designed for the treatment of multifactorial diseases, such as DM, with the precise aim of simultaneously controlling multiple pathogenic mechanisms related to the disease and providing a more effective and safer therapeutic treatment compared to combinations of selective drugs. Starting from our previous findings that highlighted the possibility to target both aldose reductase (AR) and protein tyrosine phosphatase 1B (PTP1B), two enzymes strictly implicated in the development of DM and its complications, we synthesised 3-(5-arylidene-4-oxothiazolidin-3-yl)propanoic acids and analogous 2-butenoic acid derivatives, with the aim of balancing the effectiveness of dual AR/PTP1B inhibitors which we had identified as designed multiple ligands (DMLs). Out of the tested compounds, 4f exhibited well-balanced AR/PTP1B inhibitory effects at low micromolar concentrations, along with interesting insulin-sensitizing activity in murine C2C12 cell cultures. The SARs here highlighted along with their rationalization by in silico docking experiments into both target enzymes provide further insights into this class of inhibitors for their development as potential DML antidiabetic candidates.

Dual Targeting of PTP1B and Aldose Reductase with Marine Drug Phosphoeleganin: A Promising Strategy for Treatment of Type 2 Diabetes

“…Based on the above, the potential of facing the complex and multifactorial T2DM disease by combining two selective inhibitors into one molecule with dual PTP1B and AR modulator activity is evident. A dual inhibitor of the PTP1B and AR enzymes could be useful to treat both the condition of insulin resistance and chronic complications associated with T2DM [18][19][20].…”

“…Drugs 2021, 19, x FOR PEER REVIEW 3 of 16 the above, the potential of facing the complex and multifactorial T2DM disease by combining two selective inhibitors into one molecule with dual PTP1B and AR modulator activity is evident. A dual inhibitor of the PTP1B and AR enzymes could be useful to treat both the condition of insulin resistance and chronic complications associated with T2DM [18][19][20]. T2DM is spreading rapidly, not only in industrialised countries, but also in developing ones, where the economic resources available to tackle this pandemic are very limited [21].…”

Design of Improved Antidiabetic Drugs: A Journey from Single to Multitarget Agents

“…Further in vivo studies, combined with SAR results and molecular docking studies could lead to more effective dual ALR 2 /PTP-1B inhibitors. [99,100]…”

“…Results showed increased insulin receptor phosphorylation (due to the presence of insulin), proving its ability to decrease insulin resistance. Further in vivo studies, combined with SAR results and molecular docking studies could lead to more effective dual ALR 2 /PTP‐1B inhibitors [99,100] …”

A comprehensive review on the antidiabetic attributes of thiazolidine‐4‐ones: Synthetic strategies and structure–activity relationships

“…Therefore, thiazolidine-4-one could serve as an important lead for the design of AR inhibitors as described by Maccari and Ottana et al [87,88] 2. a high activity towards long-chain substrates. [99,100] The hydrolysis of the substrates takes place by splitting the bond present between anomeric carbon and glycosidic oxygen (C 1 -O).…”