A new series of hydrazones as small‐molecule aldose reductase inhibitors. Issue 4 (5th January 2023)

• Record Type: Journal Article
• Authors: Altıntop, Mehlika D.; Demir, Yeliz; Türkeş, Cüneyt; Öztürk, Remzi B.; Cantürk, Zerrin; Beydemir, Şükrü; Özdemir, Ahmet
• Is Part Of: Archiv der Pharmazie. Volume 356:Issue 4(2023)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2023-01-05
• Subjects: aldose reductase -- hydrazone -- molecular docking -- polyol pathway -- tetrazole; Pharmaceutical chemistry -- Periodicals; Pharmacology -- Periodicals; 615.19
• DOI: 10.1002/ardp.202200570
• Languages: English
• ISSNs: 0365-6233

Abstract

Abstract: 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 K i values ranging between 0.177 and 6.322 µM and IC50 values ranging between 0.210 and 0.676 µM. 2‐[(1‐(4‐Hydroxyphenyl)‐1 H ‐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 ( K i = 0.177 µM) compared to epalrestat ( K i = 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. Abstract : New tetrazole‐hydrazone hybrids (1–15 ) were synthesized and subjected to an in vitro assay to assess their aldose reductase (AR) inhibitory profiles. Compound 4 was found to be the most potent inhibitor of AR in this series with an IC50 value of 0.297 µM in a competitive manner ( K i = 0.177 µM). In silico data also supported the in vitro data.