Abstract
Abstract In an effort to identify potent aldose reductase (AR) inhibitors, 5-(arylidene)thiazolidine-2,4-diones (1–8), which were prepared by the solvent-free reaction of 2,4-thiazolidinedione with aromatic aldehydes in the presence of urea, were examined for their in vitro AR inhibitory activities and cytotoxicity. 5-(2-Hydroxy-3-methylbenzylidene)thiazolidine-2,4-dione (3) was the most potent AR inhibitor in this series, exerting uncompetitive inhibition with a K i value of 0.445 ± 0.013 µM. The IC50 value of compound 3 for L929 mouse fibroblast cells was determined as 8.9 ± 0.66 µM, pointing out its safety as an AR inhibitor. Molecular docking studies suggested that compound 3 exhibited good affinity to the binding site of AR (PDB ID: 4JIR). Based upon in silico absorption, distribution, metabolism, and excretion data, the compound is predicted to have favorable pharmacokinetic features. Taking into account the in silico and in vitro data, compound 3 stands out as a potential orally bioavailable AR inhibitor for the management of diabetic complications as well as nondiabetic diseases.
Highlights
In an effort to identify potent aldose reductase (AR) inhibitors, 5-(arylidene)thiazolidine-2,4-diones (1–8), which were prepared by the solvent-free reaction of 2,4thiazolidinedione with aromatic aldehydes in the presence of urea, were examined for their in vitro AR inhibitory activities and cytotoxicity. 5-(2-Hydroxy-3-methylbenzylidene)thiazolidine-2,4-dione (3) was the most potent AR inhibitor in this series, exerting uncompetitive inhibition with a Ki value of 0.445 ± 0.013 μM
Taking into account the knowledge obtained so far [5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26] and the potential of TZD-based small molecules as AR inhibitors [14,15,16,17,18,19,20,21,22,23,24,25,26], we reported the preparation of new 2,4-TZDs and in vitro studies related to their AR inhibitory activities and cytotoxicity toward L929 mouse fibroblast cell line
In the search for AR inhibitors for the management of Type 2 diabetes (T2D) and its complications, the identification of potent therapeutic agents endowed with favorable pharmacokinetic profiles as well as devoid of severe unwanted effects is an uphill task for researchers [5]
Summary
Abstract: In an effort to identify potent aldose reductase (AR) inhibitors, 5-(arylidene)thiazolidine-2,4-diones (1–8), which were prepared by the solvent-free reaction of 2,4thiazolidinedione with aromatic aldehydes in the presence of urea, were examined for their in vitro AR inhibitory activities and cytotoxicity. 5-(2-Hydroxy-3-methylbenzylidene)thiazolidine-2,4-dione (3) was the most potent AR inhibitor in this series, exerting uncompetitive inhibition with a Ki value of 0.445 ± 0.013 μM. Apart from its role in T2D complications, AR is an important mediator in oxidative and inflammatory-signaling pathways implicated in the pathophysiology of cardiovascular disorders, sepsis, and cancer In this context, AR is identified as a multidisease target for the design of potent agents able to counteract the development of long-term T2D complications as well as nondiabetic diseases [5,6,7,8,9,10,11,12,13]. Distribution, metabolism, and excretion (ADME) studies were carried out to estimate their physicochemical parameters for the evaluation of their oral bioavailability and drug likeness
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
