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

In this work, a series of 2H-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 in vitro 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 2H-benzoxaborinine 2a with hCA I and hCA II revealed significant differences compared with the 1H-benzoxaborinine analogue, which can be attributed to the increased structural rigidity of the scaffold. Finally, the selected compounds (2a, 3d, 5c, and 9c) were further evaluated for their in vitro antiproliferative activity against human triple-negative breast cancer (MDA-MB-231) and glioblastoma (U87MG) cancer cell lines, with derivative 5c demonstrating superior antiproliferative activity compared with the antitumor CA inhibitor SLC-0111.