Unraveling the Potential of Amino‑, Acylamino‑, and Ureido-Substituted 3H‑1,2-Benzoxaphosphepine 2‑Oxides toward Nanomolar Inhibitors of Tumor-Associated Carbonic Anhydrases IX and XII.

3H-1,2-Benzoxaphosphepine 2-oxides were recently identified as a novel class of carbonic anhydrase (CA) inhibitors. In this study, which aims to broaden the chemical space around this scaffold and improve inhibition potency against cancer-related isoforms (CA IX and CA XII), we report the synthesis and biochemical evaluation of amino-, acylamino-, and ureido-substituted benzoxaphosphepine oxides 2-4. All members of these series showed no off-target inhibition of cytosolic CA I and CA II activity, while the inhibition of the target isoforms was strongly dependent on the substitution pattern. To our delight, several compounds managed to inhibit tumor-associated CA isoforms at the nanomolar level, which is equal to or even surpasses that of the reference drugs. The results of the current study bolster and extend previous research, demonstrating the capability of the benzoxaphosphepine oxide chemotype to serve as a platform for the future development of new therapeutic agents.