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.

Automated summary

For the discovery of novel carbonic anhydrase inhibitors for cancer treatment, a series of 4-{4-[(hydroxyimino)-methyl]piperazin-1-yl}benzenesulfonamides were designed and synthesized. The compounds 27-34 showed inhibition against human isoforms hCA I, hCA II, hCA IX, and hCA XII. Compound 29 inhibited hCA I with a Ki value of 3.0 nM, while compound 32 inhibited hCA II with a Ki value of 4.4 nM. Compound 30 effectively inhibited the tumor-associated hCA IX isoform with a Ki value of 43 nM, and compounds 29 and 31 significantly inhibited hCA XII with a Ki value of 5 nM. Molecular modeling revealed the hydrophobic and hydrogen bond interactions of drug molecule 30 with the active site of the investigated hCAs, as well as its binding to zinc through the deprotonated sulfonamide group.