Expanding the Inhibitory Potential of the Benzoxaborinine Scaffold against Carbonic Anhydrases: Synthesis, Structural Characterization, and <i>In Vitro</i> Antitumor Activity

In this work, a series of 2<i>H</i>-benzoxaborinines was synthesized via an "aromatic metamorphosis" strategy based on the nickel-catalyzed insertion of boron into benzofuran scaffolds and were evaluated as novel carbonic anhydrase (CA) inhibitors. All compounds were evaluated <i>in vitro</i> against seven human CA isoforms (I, II, IV, VA, VII, IX, and XII), with several derivatives displaying low-nanomolar inhibitory activity. X-ray crystallographic analysis of the complexes of 2<i>H</i>-benzoxaborinine <b>2a</b> with hCA I and hCA II revealed significant differences compared with the 1<i>H</i>-benzoxaborinine analogue, which can be attributed to the increased structural rigidity of the scaffold. Finally, the selected compounds (<b>2a</b>, <b>3d</b>, <b>5c</b>, and <b>9c</b>) were further evaluated for their <i>in vitro</i> antiproliferative activity against human triple-negative breast cancer (MDA-MB-231) and glioblastoma (U87MG) cancer cell lines, with derivative <b>5c</b> demonstrating superior antiproliferative activity compared with the antitumor CA inhibitor SLC-0111.