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 <b>27</b>-<b>34</b> 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 <b>29</b> with a <i>K</i><sub>i</sub> value of 3.0 nM, whereas hCA II was inhibited by compound <b>32</b> with a <i>K</i><sub>i</sub> value of 4.4 nM. The tumor-associated hCA IX isoform was inhibited by compound <b>30</b> effectively with an <i>K</i><sub>i</sub> value of 43 nM, whereas the activity of another cancer-related isoform, hCA XII, was significantly inhibited by <b>29</b> and <b>31</b> with a <i>K</i><sub>i</sub> value of 5 nM. Molecular modeling showed that drug molecule <b>30</b> 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.