Novel quinazolinone-based 2,4-thiazolidinedione-3-acetic acid derivatives as potent aldose reductase inhibitors

Abstract

Aim: Targeting aldose reductase enzyme with 2,4-thiazolidinedione-3-acetic acid derivatives having a bulky hydrophobic 3-arylquinazolinone residue.

Materials & methods: All the target compounds were structurally characterized by different spectroscopic methods and microanalysis, their aldose reductase inhibitory activities were evaluated, and binding modes were studied by molecular modeling.

Results: All the synthesized compounds proved to inhibit the target enzyme potently, exhibiting IC₅₀ values in the nanomolar/low nanomolar range. Compound 5i (IC₅₀ = 2.56 nM), the most active of the whole series, turned out to be almost 70-fold more active than the only marketed aldose reductase inhibitor epalrestat.

Conclusion: This work represents a promising matrix for developing new potential therapeutic candidates for prevention of diabetic complications through targeting aldose reductase enzyme. [Formula: see text].

Keywords: 2,4-Thiazolidinedione-3-acetic acids; aldose reductase inhibitors; diabetic complications; molecular dynamics; molecular modeling.