Novel benzenesulfonamides containing a dual triazole moiety with selective carbonic anhydrase inhibition and anticancer activity

Abstract

A series of sulfonamides incorporating a 1,2,3-triazolyloxime substituted 1,2,3-triazolyl moiety were conceptualized and synthesized as human carbonic anhydrase (<i>h</i>CA) inhibitors. The synthesized small structures, denoted 7a through 7o, exhibited moderate inhibitory effects against the tumor-associated isoforms <i>h</i>CA IX and <i>h</i>CA XII compared to the well-known <i>h</i>CA inhibitor acetazolamide. In contrast, these molecules demonstrated higher potency and a diverse range of selectivity against the cytosolic isoforms <i>h</i>CA I and <i>h</i>CA II. Notably, the 4-hydroxyphenyl derivative (compound 7d<i>versus</i> cytosolic isoforms), the 4-acetylphenyl derivative (compound 7o), and the phenyl derivative (compound 7a) emerged as the most potent and selective inhibitors in this series, with inhibition constants (<i>K</i> _I) of 47.1, 35.9, 170.0, and 149.9 nM, respectively, against <i>h</i>CA I, II, IX, and XII. Further cytotoxicity assays of compounds 7a-o against cancer cell lines Hep3B and A549, as well as normal cell line L929, were conducted to assess their selectivity towards malignant cells. Compounds 7d, 7g, and 7k exhibited selective cytotoxicity towards the Hep3B cell line, with reduced selectivity towards A549, whereas compound 7j demonstrated higher selectivity for the A549 cell line. Additionally, molecular docking studies were performed to elucidate the binding modes of these compounds within the active sites of <i>h</i>CAs, revealing crucial interactions that underpin their significant activity and selectivity for the tumor-specific isoforms.