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  • Title: Identification of a new class of potent aldose reductase inhibitors: Design, microwave-assisted synthesis, in vitro and in silico evaluation of 2-pyrazolines.
    Author: Sever B, Altıntop MD, Demir Y, Yılmaz N, Akalın Çiftçi G, Beydemir Ş, Özdemir A.
    Journal: Chem Biol Interact; 2021 Aug 25; 345():109576. PubMed ID: 34252406.
    Abstract:
    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.
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