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., Yilmaz N., AKALIN ÇİFTÇİ G., BEYDEMİR Ş., ...Daha Fazla

CHEMICO-BIOLOGICAL INTERACTIONS, cilt.345, 2021 (SCI-Expanded) identifier 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, BIOLOGICAL EVALUATION, CARBONIC-ANHYDRASE, MOLECULAR DOCKING, DERIVATIVES, ACETYLCHOLINESTERASE, COMPLICATIONS, TOXICITY, ENZYME, AGENTS
  • Anadolu 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-(4fluorophenyl)-2-pyrazoline (20) was identified as the most promising AR inhibitor with an IC50 value of 0.160 +/- 0.005 mu M exerting competitive inhibition with a Ki value of 0.019 +/- 0.001 mu M as compared to epalrestat (IC50 = 0.279 +/- 0.001 mu M; Ki = 0.801 +/- 0.023 mu M) and quercetin (IC50 = 4.120 +/- 0.123 mu M; Ki = 6.082 +/- 0.272 mu M). Compound 20 displayed cytotoxicity towards L929 cells with an IC50 value of 18.75 +/- 1.06 mu M highlighting its safety as an AR inhibitor. Molecular docking studies suggested that 7C-7C 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 nondiabetic diseases.