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

TL;DR

This study identifies new compounds that strongly inhibit specific carbonic anhydrase enzymes linked to cancer, with some showing better selectivity than existing drugs.

Contribution

The paper introduces novel N-aryl-2-(4-sulfamoylphenyl)hydrazine-1-carbothioamide derivatives with improved selectivity for hCA IX and XII.

Findings

Compound 3h showed 37-fold selectivity for hCA II over hCA I and 2.5-fold higher activity than acetazolamide.

Compound 3l demonstrated improved selectivity for hCA IX compared to standard drugs.

Compound 3a inhibited hCA XII with high potency and selectivity over other isoforms.

Abstract

Background: 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. Methods: A library of twelve novel N-aryl-2-(4-sulfamoylphenyl)hydrazine-1-carbothioamides 3 along with two new N-aryl-2-(4-sulfamoylphenyl)hydrazine-1-carboxamide derivatives 5 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. Results: All compounds exhibited potent inhibition of the tested isoforms in the nanomolar range. Compound 3i showed the highest inhibition of hCA I activity but demonstrated poor selectivity toward the other isoforms. Compound 3h 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, 3l (Ki = 32.1 nM) demonstrated markedly improved selectivity for hCA IX over hCA I, II, and XII relative to the standard drug. Notably, compound 3a showed the most potent inhibition against hCA XII (Ki = 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). Conclusions: The present study suggests potent lead compounds as selective hCA IX and XII inhibitors with anticancer activity.

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