Design, synthesis, and aldose reductase inhibitory effect of some novel carboxylic acid derivatives bearing 2-substituted-6-aryloxo-pyridazinone moiety

Akdağ M., ÖZÇELİK A. B., Demir Y., Beydemir Ş.

Journal of Molecular Structure, cilt.1258, 2022 (SCI-Expanded) identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 1258
  • Basım Tarihi: 2022
  • Doi Numarası: 10.1016/j.molstruc.2022.132675
  • Dergi Adı: Journal of Molecular Structure
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, Chimica, Compendex, INSPEC
  • Anahtar Kelimeler: Aldose reductase, Diabetes mellitus, Pyridazinone, Polyol pathway, Inflammation, Carboxylic Acid, 3(2H)-PYRIDAZINONE, PROTEIN
  • Gazi Üniversitesi Adresli: Evet

Özet

© 2022 Elsevier B.V.The polyol pathway is a two-step metabolic pathway in which glucose is reduced to sorbitol and then converted to fructose. The first and rate limiting enzyme of this pathway, aldose reductase (ALR2), is a drug target for treating diabetic complications and inflammation. Given the common features of the known inhibitors, we designed a series of pyridazinone bearing benzoic acid derivatives and then we carried the carboylic acid group onto pyridazinone and synthesized them. We evaluated the compounds against ALR2. Our results showed that all the compounds showed submicromolar or low micromolar inhibitory activity against ALR2. Compound 1 and 3 were found more active than the reference compound (epalrestat) with IC50 values of 0.278 µM (Ki=0.042±0.006 µM, competitive) and 0.188 µM (Ki=0.024±0.001 µM, competitive) respectively. Moreover, non carboxylic acid derivative 16c and the ester counterparts of 1, 3, and 12 (1c, 3c, and 12c) showed submicromolar activity against ALR2. According the results, we are able to establish some SARs in order to use in our further studies.