Multi-Target Glitazones for Modulating Peroxisome Proliferator-Activated Receptor-γ, Cyclooxygenase-2, and Carbonic Anhydrases for the Management of Metabolic Dysfunction

In light of the significant correlation between inflammatory alterations and metabolic dysfunction throughout different stages of metabolic disease progression, we focused on utilizing our previously characterized glitazone-derived anti-inflammatory 1,2,3-triazoles as lead compounds to create new multitarget directed ligands that interact with COX-2, peroxisome proliferator-activated receptor γ (PPARγ), and CA within the framework of metabolic disorders. Notably, seven compounds exhibited equivalent or similar COX-2 inhibitory effects to celecoxib. Four compounds, namely, 3b, 3e, 5e, and 5h, exhibited substantial nanomolar inhibitory effects against hCA I, II, IV, and IX isoforms (K_i 8.5–833, 0.37–24.6, 44.2–777, and 27.3–32.1 nM, respectively). Furthermore, compounds 5e and 5h demonstrated a significant increase in glucose uptake in the rat hemidiaphragm experiment, outperforming pioglitazone. A robust PPARγ agonism in luciferase assay, full-length human PPARγ transactivation without artificially increasing its expression, and isothermal titration calorimetry for K_d determination were used to substantiate their PPARγ-dependent insulin-sensitizing activity. In vivo pharmacokinetic and tissue distribution experiments were carried out, revealing favorable properties. The in vitro activities were reflected into effective in vivo anti-inflammatory potential in the formalin-induced rat paw edema assay, and they also exhibited a favorable ulcerogenic profile. Furthermore, computational target prediction and network pharmacology analysis for the two most active molecules, 5e and 5h, identified important biological pathways associated with the intended outcomes. In this regard, 5e and 5h not only mitigated hyperglycemia and insulin resistance in an in vivo rat model of type 2 diabetes but also protected against renal and lipemic damage caused by metabolic dysfunction. Finally, docking simulations indicated potential binding interactions with the intended biological targets.