Hybridization Approach Applied to Umbelliferon and Vanilloids toward New Inhibitors of Carbonic Anhydrases IX and XII with In Vitro Antiproliferative and Anti-inflammatory Activities

Human carbonic anhydrases (hCAs) IX and XII have emerged as promising therapeutic targets and are overexpressed in hypoxic tumors. Leveraging the chemotype of umbelliferon (<b>UMB</b>), as a selective hCAs IX and XII inhibitor, we designed and synthesized several hybrids (<b>7</b>-<b>33</b>) connecting <b>UMB</b> natural scaffold with vanilloids by using methylene spacers or triazole linkers. These hybrids demonstrated nanomolar inhibitory activity against the tumor-associated hCAs IX and XII. Molecular modeling and dynamics simulations revealed stable hydrogen bonding and hydrophobic interactions. In vitro evaluation of human bronchial epithelial (BEAS-2B) and lung adenocarcinoma (A549) cell lines showed selective cytotoxicity against cancer cells. Selected compounds induced G1 cell cycle arrest, reduced expression of the metastasis-associated markers CD9 and epithelial cell adhesion molecule, and exhibited cytoprotective and anti-inflammatory effects in BEAS-2B cells. Collectively, these findings identify <b>UMB</b>-vanilloid hybrids as promising candidates for the development of novel therapeutics for nonsmall cell lung cancer.