Investigation on N-Aryl-2-(4-sulfamoylphenyl)hydrazine-1-carbothioamide as Human Carbonic Anhydrases Inhibitors

<b>Background</b>: Among the 15 human (h) carbonic anhydrase (CA; EC 4.2.1.1) isoforms, hCA IX and XII are particularly important due to their roles in tumor cell growth and survival, identifying them as promising targets for anticancer therapy. As a result, considerable effort has been directed toward the development of novel inhibitors that are highly selective for these isoforms. <b>Methods</b>: A library of twelve novel <i>N</i>-aryl-2-(4-sulfamoylphenyl)hydrazine-1-carbothioamides <b>3</b> along with two new <i>N</i>-aryl-2-(4-sulfamoylphenyl)hydrazine-1-carboxamide derivatives <b>5</b> were synthesized and their inhibition abilities were tested against four human carbonic anhydrase isozymes (hCA I, II, IX and XII) related to some global diseases including glaucoma, cancer and osteoporosis. <b>Results</b>: All compounds exhibited potent inhibition of the tested isoforms in the nanomolar range. Compound <b>3i</b> showed the highest inhibition of hCA I activity but demonstrated poor selectivity toward the other isoforms. Compound <b>3h</b> displayed superior selectivity for hCA II over hCA I (hCA I/II = 37) and exhibited 2.5-fold higher inhibitory activity compared to acetazolamide (AAZ). Among the tested compounds, <b>3l</b> (<i>K</i>_i = 32.1 nM) demonstrated markedly improved selectivity for hCA IX over hCA I, II, and XII relative to the standard drug. Notably, compound <b>3a</b> showed the most potent inhibition against hCA XII (<i>K</i>_i = 6.8 nM), comparable to AAZ, while exhibiting significantly greater selectivity over off-target isoforms and the other tumor-associated isozyme (hCA IX/XII = 20 versus hCA IX/XII = 4.5 for AAZ). <b>Conclusions</b>: The present study suggests potent lead compounds as selective hCA IX and XII inhibitors with anticancer activity.