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 compounds27–34were investigated for the inhibition of human (h) isoforms hCA I,
hCA II, hCA IX, and hCA XII. The hCA I was inhibited
by compound29with aKivalue
of 3.0 nM, whereas hCA II was inhibited by compound32with aKivalue of 4.4 nM. The tumor-associated
hCA IX isoform was inhibited by compound30effectively
with anKivalue of 43 nM, whereas the
activity of another cancer-related isoform, hCA XII, was significantly
inhibited by29and31with aKivalue of 5 nM. Molecular modeling showed that drug molecule30participates in significant hydrophobic and hydrogen bond
interactions with the active site of the investigated hCAs and binds
to zinc through the deprotonated sulfonamide group.