2,4-thiazolidinedione (TZD) scaffold is a synthetic versatile scaffold explored by medicinal
chemists for the discovery of novel molecules for the target-specific approach to treat or manage
number of deadly ailments. PTP 1B is the negative regulator of insulin signaling cascade, and its diminished
activity results in abolishment of insulin resistance associated with T2DM. The present review
focused on the seven years journey (2012-2018) of TZDs as PTP 1B inhibitors with the insight
into the amendments in the structural framework of TZD scaffold in order to optimize/design potential
PTP 1B inhibitors. We have investigated the synthesized molecules based on TZD scaffold with potential
activity profile against PTP 1B. Based on the SAR studies, the combined essential pharmacophoric
features of selective and potent TZDs have been mapped and presented herewith for further design and
synthesis of novel inhibitors of PTP 1B. Compound 46 bearing TZD scaffold with N-methyl benzoic
acid and 5-(3-methoxy-4-phenethoxy) benzylidene exhibited the most potent activity (IC50 1.1 µM).
Imidazolidine-2,4-dione, isosteric analogue of TZD, substituted with 1-(2,4-dichlorobenzyl)-5-(3-(2,4-
dichlorobenzyloxy)benzylidene) (Compound 15) also endowed with very good PTP inhibitory activity
profile (IC50 0.57 µM). It is noteworthy that Z-configuration is essential in structural framework
around the double bond of arylidene for the designing of bi-dentate ligands with optimum activity.
Keywords: Imidazolidinedione, insulin resistance, insulin signaling cascade, protein tyrosine phosphatase (PTP 1B), thiazolidinediones,
type 2 diabetes mellitus (T2DM).
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