Design and synthesis of potent and selective aldose reductase inhibitors based on pyridylthiadiazine scaffold

A series of pyrido[2,3-e]-[1,2,4]-thiadiazine 1,1-dioxide acetic acid derivatives were synthesized and tested for their inhibitory activity against aldose reductase (ALR2). These derivatives were found to be potent aldose reductase inhibitors with IC50 values ranging from 0.038 μM to 11.29 μM. Most but not all of them showed a strong ALR2 inhibition activity and significant selectivity, which were further supported by docking studies. Of these inhibitors, compound 7d exhibited highest inhibition activity. Structure–activity relationship studies indicate the requirement of N2-benzyl group with electron-withdrawing substituents and N4-acetic acid group in the pyridothiadiazine scaffold.

Graphical abstractA series of pyrido[2,3-e]-[1,2,4]-thiadiazine derivatives were synthesized and found to be potent aldose reductase inhibitors with IC50 values ranging from 0.038 to 11.29 μM. Their structure–activity relationships were also discussed.Figure optionsDownload full-size imageDownload as PowerPoint slideHighlights► Aldose reductase links with the long-term diabetic complications. ► Aldose reductase inhibitors are a promising and an attractive therapeutic strategy. ► Design based on pyridothiadiazine scaffold leads to potent and selective inhibitors.