A Journey Around Boronic Acids: Sulfonyl Hydrazone-Containing Derivatives as Carbonic Anhydrase Inhibitors

Recently, a rising interest in boronic acids and their derivatives was recorded in the Medicinal Chemistry field due to their high versatility and broad applicability as bioactive compounds in several diseases, including cancer and microbial infections. The ability of boronic acid moieties to bind zinc ions was first hypothesized by the inhibitory activity of bortezomib, a boron-containing protease inhibitor, on different isoforms of the Carbonic Anhydrase (CA, EC: 4.2.1.1) enzyme family and then assessed through X-ray crystallographic studies on benzoxaboroles in complex with hCA II. These findings, along with the overexpression of isoforms IX and XII in hypoxic cancer and, in particular, breast cancer, drove us to explore the chemical space around the phenylboronic acids by generating a focused library of 16 derivatives (1–4a–d) decorated with alkyl sulfonyl hydrazones. The compounds were then subjected to stopped flow-based inhibition assays on a panel of hCAs, including the tumor-associated isoforms, revealing low micromolar inhibition constants (KIs) in some cases. However, antiproliferative assays conducted on a human triple-negative breast cancer cell line showed a lack of activity at the tested concentrations.