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  • Title: A new series of hydrazones as small-molecule aldose reductase inhibitors.
    Author: Altıntop MD, Demir Y, Türkeş C, Öztürk RB, Cantürk Z, Beydemir Ş, Özdemir A.
    Journal: Arch Pharm (Weinheim); 2023 Apr; 356(4):e2200570. PubMed ID: 36603162.
    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 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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