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, <b>3b</b>, <b>3e</b>, <b>5e</b>, and <b>5h</b>, exhibited substantial nanomolar inhibitory effects against <i>h</i>CA I, II, IV, and IX isoforms (<i>K</i> _<i>i</i> 8.5-833, 0.37-24.6, 44.2-777, and 27.3-32.1 nM, respectively). Furthermore, compounds <b>5e</b> and <b>5h</b> 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 <i>K</i> _d determination were used to substantiate their PPARγ-dependent insulin-sensitizing activity. <i>In vivo</i> pharmacokinetic and tissue distribution experiments were carried out, revealing favorable properties. The <i>in vitro</i> activities were reflected into effective <i>in vivo</i> 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, <b>5e</b> and <b>5h</b>, identified important biological pathways associated with the intended outcomes. In this regard, <b>5e</b> and <b>5h</b> not only mitigated hyperglycemia and insulin resistance in an <i>in vivo</i> 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.