Non-acidic bifunctional benzothiazole-based thiazolidinones with antimicrobial and aldose reductase inhibitory activity as a promising therapeutic strategy for sepsis

Sepsis is a life-threatening disease that affects millions of people worldwide. Microbial infections that lead to sepsis syndrome are associated with an increased production of inflammatory molecules. Aldose Reductase has recently emerged as a molecular target that is involved in various inflammatory diseases, including sepsis. Herein, a series of previously synthesized benzothiazole-based thiazolidinones that exhibited strong Antibacterial and Antifungal activities has been evaluated for inhibition efficacy against Aldose Reductase and selectivity toward aldehyde reductase under in vitro conditions. The most promising inhibitor 5 was characterized with IC₅₀ value of 3.99 μM and a moderate selectivity. Molecular docking simulations revealed the binding mode of compounds at the active site of human Aldose Reductase. Moreover, owning to the absence of an acidic pharmacophore, good membrane permeation of the novel Aldose Reductase inhibitors was predicted. Excellent "drug-likeness" was assessed for most of the compounds by applying the criteria of Lipinski's "rule of five".