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

ALTINTOP M. D., Demir Y., TÜRKEŞ C., ÖZTÜRK BAŞPINAR N., CANTÜRK Z., BEYDEMİR Ş., ...Daha Fazla

Archiv der Pharmazie, cilt.356, sa.4, 2023 (SCI-Expanded) identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 356 Sayı: 4
  • Basım Tarihi: 2023
  • Doi Numarası: 10.1002/ardp.202200570
  • Dergi Adı: Archiv der Pharmazie
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, BIOSIS, CAB Abstracts, Chemical Abstracts Core, Chimica, EMBASE, International Pharmaceutical Abstracts, Veterinary Science Database
  • Anahtar Kelimeler: aldose reductase, hydrazone, molecular docking, polyol pathway, tetrazole
  • Bilecik Şeyh Edebali Üniversitesi Adresli: Evet

Özet

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.