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A new series of hydrazones as small-molecule aldose reductase inhibitors

In the search for small-molecule aldose reductase (AR) inhibitors, new tetrazole-hydrazone hybrids (1-15) were designed. An efficient procedure was employed for the synthesis of compounds 1-15. All hydrazones were subjected to an in vitro assay to assess their AR inhibitory profiles. Compounds 1-15 caused AR inhibition with Ki values ranging between 0.177 and 6.322 µM and IC50 values ranging between 0.210 and 0.676 µM. 2-[(1-(4-Hydroxyphenyl)-1H-tetrazol-5-yl)thio]-N'-(4-fluorobenzylidene)acetohydrazide (4) was the most potent inhibitor of AR in this series. Compound 4 markedly inhibited AR (IC50 = 0.297 µM) in a competitive manner (Ki = 0.177 µM) compared to epalrestat (Ki = 0.857 µM, IC50 = 0.267 µM). Based on the in vitro data obtained by applying the MTT test, compound 4 showed no cytotoxic activity toward normal (NIH/3T3) cells at the tested concentrations, indicating its safety as an AR inhibitor. Compound 4 exhibited proper interactions with crucial amino acid residues within the active site of AR. In silico QikProp data of all hydrazones (1-15) were also determined to assess their pharmacokinetic profiles. Taken together, compound 4 stands out as a promising inhibitor of AR for further in vivo studies.

 

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The passage describes a study focused on designing and synthesizing new tetrazole-hydrazone hybrids as aldose reductase (AR) inhibitors. The study also evaluated the AR inhibitory profiles of these compounds in vitro and assessed their cytotoxicity and pharmacokinetic properties.

The results show that compounds 1-15 caused AR inhibition with Ki values ranging between 0.177 and 6.322 µM and IC50 values ranging between 0.210 and 0.676 µM. Compound 4, 2-[(1-(4-Hydroxyphenyl)-1H-tetrazol-5-yl)thio]-N'-(4-fluorobenzylidene)acetohydrazide, was the most potent inhibitor of AR in this series, with an IC50 of 0.297 µM and a Ki of 0.177 µM. Compound 4 also showed no cytotoxic activity toward normal (NIH/3T3) cells at the tested concentrations, indicating its safety as an AR inhibitor. In addition, compound 4 exhibited proper interactions with crucial amino acid residues within the active site of AR.

The study also used in silico QikProp data to assess the pharmacokinetic profiles of all hydrazones (1-15), providing additional information on their drug-like properties.

Overall, the study suggests that compound 4 is a promising AR inhibitor for further in vivo studies, based on its potency, safety, and interactions with AR.

Related Products

Cat.No. Product Name Information
S2035 Epalrestat Epalrestat is an aldose reductase inhibitor with IC50 of 72 nM.

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Carbohydrate Metabolism Aldose Reductase