Identification of a New Class of Potent Aldose Reductase Inhibitors: Design, Microwave-assisted Synthesis, in Vitro and in Silico Evaluation of 2-pyrazolines

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 IC value of 0.160 ± 0.005 μM exerting competitive inhibition with a K value of 0.019 ± 0.001 μM as compared to epalrestat (IC = 0.279 ± 0.001 μM; K = 0.801 ± 0.023 μM) and quercetin (IC = 4.120 ± 0.123 μM; K = 6.082 ± 0.272 μM). Compound 20 displayed cytotoxicity towards L929 cells with an IC 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.