Identification of a new class of potent aldose reductase inhibitors: Design, microwave-assisted synthesis, in vitro and in silico evaluation of 2-pyrazolines

SEVER B., ALTINTOP M. D., Demir Y., Yılmaz N., AKALIN ÇİFTÇİ G., BEYDEMİR Ş., ...Daha Fazla

Chemico-Biological Interactions, cilt.345, 2021 (SCI-Expanded) identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 345
  • Basım Tarihi: 2021
  • Doi Numarası: 10.1016/j.cbi.2021.109576
  • Dergi Adı: Chemico-Biological Interactions
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, BIOSIS, CAB Abstracts, Chemical Abstracts Core, EMBASE, MEDLINE, Veterinary Science Database
  • Anahtar Kelimeler: Aldose reductase, Cytotoxicity, Microwave-assisted synthesis, Molecular docking, Pyrazoline
  • Bilecik Şeyh Edebali Üniversitesi Adresli: Evet

Özet

Aldose reductase (AR) acts as a multi-disease target for the design and development of therapeutic agents for the management of diabetic complications as well as non-diabetic diseases. In the search for potent AR inhibitors, the microwave-assisted synthesis of twenty new compounds with a 1,3-diaryl-5-(4-fluorophenyl)-2-pyrazoline moiety as a common fragment in their structure (1–20) was carried out efficiently. Compounds 1–20 were subjected to in vitro studies, which were conducted to assess their AR inhibitory effects and cytotoxicity towards L929 mouse fibroblast (normal) cells. Among these compounds, 1-(3-bromophenyl)-3-(4-piperidinophenyl)-5-(4-fluorophenyl)-2-pyrazoline (20) was identified as the most promising AR inhibitor with an IC50 value of 0.160 ± 0.005 μM exerting competitive inhibition with a Ki value of 0.019 ± 0.001 μM as compared to epalrestat (IC50 = 0.279 ± 0.001 μM; Ki = 0.801 ± 0.023 μM) and quercetin (IC50 = 4.120 ± 0.123 μM; Ki = 6.082 ± 0.272 μM). Compound 20 displayed cytotoxicity towards L929 cells with an IC50 value of 18.75 ± 1.06 μM highlighting its safety as an AR inhibitor. Molecular docking studies suggested that π-π stacking interactions occurred between the m-bromophenyl moiety of compound 20 and Trp21. Based on in silico pharmacokinetic studies, compound 20 was found to possess favorable oral bioavailability and drug-like properties. It can be concluded that compound 20 is a potential orally bioavailable AR inhibitor for the management of diabetic complications as well as non-diabetic diseases.