article · ACS Pharmacology & Translational Science
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> <sub><i>i</i></sub> 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> <sub>d</sub> 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.
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DOI: 10.1021/acsptsci.5c00011
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