Despite advances in the treatment of Type 2 diabetes mellitus (T2DM), it is still difficult to prevent the development and progression of disabling complications associated with T2DM. It is needed to search for alternative treatments for diabetics with a single medication that will not only control the glucose level but also reduce acute complications produced by abnormal glucose concentrations. This research was dedicated to the design and synthesis of thiazolidinedione (TZD) based dual inhibitors of Aldose Reductase (AR) and Protein Tyrosine Phosphatase 1B (PTP 1B) for the management of diabetes and associated complications. Molecular docking assisted 3D-QSAR study was performed distinctly on two different datasets comprising TZD based AR (57 molecules) and PTP inhibitors (80 molecules) using CADD tools. Based on favourable pharmacophoric features against AR and PTP 1B, a series of novel TZDs (4a-d) were synthesized. TZDs were evaluated for their in vitro dual AR and PTP inhibitory potential, and tested for anti-hyperglycemic activity in STZ-NA induced diabetic mice. Among 4a-d, 4d emerged as most potent dual inhibitor with 88.19% of AR inhibition and 68.09% of PTP 1B inhibition at 10µM. N3-ethyl ester derivative 4c exhibited highly significant in vivo anti-hyperglycemic activity compared to control (p &lt; 0.001) and pioglitazone (p &lt; 0.01) during the study period of 28 days. The treatment with 4a-d was advantageous in term of pancreatic protection and also weight gain, a major drawback of pioglitazone treatment. The discovered molecules could be a potent alternative to clinically available oral anti-diabetics with dual benefits i.e. for the management of T2DM as well as associated complications post pre-clinical and clinical interventions. Moreover, dual inhibitor strategy may also provide significant pharmaceutical and development advantages including cost effectiveness and improved safety profile.

Discovery of novel TZD based dual inhibitors of AR and PTP 1B for the management of T2DM and associated complications

ACS Spring Meeting 2021

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