Design, Synthesis, and Biological Evaluation of Novel Dithiocarbamate-Based Human Carbonic Anhydrase IX/XII Inhibitors as Potential Anti-Glioblastoma Agents

To develop human carbonic anhydrase (hCA) IX/XII-targeted therapeutics for glioblastoma multiforme (GBM), novel dithiocarbamate (DTC)-based compounds were synthesized and evaluated for their inhibitory activity against hCA I, II, IX, and XII isoforms. The most potent hCA IX/XII inhibitors were further investigated for their cytotoxic activity against U87 and T98 glioblastoma cells, selectivity toward healthy neuronal cells, and their effects on oxidative stress, inflammatory mediators, and cell death-related pathways. Compounds 4, 9, and 30 emerged as the most promising candidates, with compounds 9 and 30 exhibiting potent cytotoxic activity against both U87 and T98 cells. These compounds acted as dual hCA IX/XII inhibitors with a clear preference for hCA XII. Compounds 9 and 30 modulated the oxidative stress-inflammation axis through regulation of cellular redox balance, and inflammation-associated mediator profiles, including IL-1β, IL-10, TNF-α, and TGF-β. Compound 4 also attenuated oxidative stress and inflammatory signaling in U87 cells. Molecular docking studies supported the experimental findings by revealing favorable binding interactions within the active sites of hCA IX and XII, providing a structural basis for their inhibitory activities. Collectively, these findings identify compounds 4, 9, and 30 as promising DTC-based compounds for GBM therapy through the combined modulation of tumor-associated CAs, oxidative stress, inflammatory, and cell death-related pathways.