Discovery of Novel Hydroxyimine-Tethered Benzenesulfonamides as Potential Human Carbonic Anhydrase IX/XII Inhibitors

[Image: see text] To discover novel carbonic anhydrase (CA, EC 4.2.1.1) inhibitors for cancer treatment, a series of 4-{4-[(hydroxyimino)methyl]piperazin-1-yl}benzenesulfonamides were designed and synthesized using SLC-0111 as the lead molecule. The developed novel compounds 27–34 were investigated for the inhibition of human (h) isoforms hCA I, hCA II, hCA IX, and hCA XII. The hCA I was inhibited by compound 29 with a K(i) value of 3.0 nM, whereas hCA II was inhibited by compound 32 with a K(i) value of 4.4 nM. The tumor-associated hCA IX isoform was inhibited by compound 30 effectively with an K(i) value of 43 nM, whereas the activity of another cancer-related isoform, hCA XII, was significantly inhibited by 29 and 31 with a K(i) value of 5 nM. Molecular modeling showed that drug molecule 30 participates in significant hydrophobic and hydrogen bond interactions with the active site of the investigated hCAs and binds to zinc through the deprotonated sulfonamide group.