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

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 synthe-sized 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 Ki value of 3.0 nM, whereas hCA II was inhibited by compound 32 with a Ki value of 4. 4 nM. The tumor-associated hCA IX isoform was inhibited by compound 30 effectively with an Ki value of 43 nM, whereas the acti v i t y of another cancer-related isoform, hCA XII, was significa n t l y inhibited by 29 and 31 with a Ki value of 5 nM. Molecula r modeling showed that drug molecule 30 participates in significant hydrophobic and hydrogen bond interactions with the ac t i v e site of the investigated hCAs and binds to zinc through the deprotonated sulfonamide group.