Research progress on 2,4-thiazolidinedione and 2-thioxo-4-thiazolidinone analogues as aldose reductase inhibitors

Diabetes-associated complications are a major global health concern. In diabetics, the increased accu-mulation of sorbitol, produced via over activated polyol pathway, from glucose by the action of aldose reductase (AR, ALR2, or AKR1B1), has been associated with life-threatening co-morbidities. Aldose reduc-tase is crucial in detoxifying certain hazardous aldehydes. However, aldose reductase overexpression in the hyperglycemic state results in microvascular and macrovascular diabetic complications through the consequences of the activated polyol pathway. Accordingly, aldose reductase inhibition has been identi-fied as a viable strategy for dealing with diabetes-associated complications, and it has been put under investigation by various researchers around the world. 2,4-Thiazolidinedione (TZD) and its bio-isosteric analog 2-thioxo-4-thiazolidinone (rhodanine) have been explored as potential inhibitors of aldose reduc-tase to find new molecules. The current review provides a comprehensive insight into the development and medicinal chemistry of TZD and rhodanine derivatives as aldose reductase inhibitors during the last twenty years (2002-2021). Here, the synthetic strategies, SAR, and binding mode of various compounds, Quantitative structure activity relationship (QSARs) are discussed with an emphasis on structural changes to the both moieties for optimizing/designing potent target-specific inhibitors, which is expected to be beneficial for the further design and discovery of newer agents for the treatment of diabetic compli-cations. In addition, the patents on TZDs and rhodanine derivatives as aldose reductase inhibitors are summarized to illustrate the current status.(c) 2022 Elsevier B.V. All rights reserved.

Automated summary

Diabetes-associated complications are a major global health concern, and aldose reductase inhibitors have been proposed as a viable strategy for dealing with these complications. This review provides a comprehensive insight into the development and medicinal chemistry of 2,4-thiazolidinedione (TZD) and rhodanine derivatives as aldose reductase inhibitors. The review discusses the synthetic strategies, structure-activity relationships (SAR), and binding mode of various compounds, with a focus on optimizing/designing potent target-specific inhibitors for the treatment of diabetic complications.