Sulphonyl thiourea compounds containing pyrimidine as dual inhibitors of I, II, IX, and XII carbonic anhydrases and cancer cell lines: synthesis, characterization and <i>in silico</i> studies

Some novel sulphonyl thiourea derivatives (7a-m) containing 4,6-diarylpyrimidine rings were designed and synthesized using a one-pot procedure. These compounds exhibited remarkable dual inhibitory activity against human carbonic anhydrase <i>h</i>CA I, <i>h</i>CA II, <i>h</i>CA IX, and XII isoenzymes and some cancer cell lines. Among them, some thioureas had significantly more potent inhibitory activities in the order of 7l > 7c > 7f (against the <i>h</i>CA I isoform), 7f > 7b > 7c (against the <i>h</i>CA II isoform), 7c > 7g > 7a > 7b (against the <i>h</i>CA IX isoform), and 7d > 7c > 7g > 7f (against the <i>h</i>CA XII isoform). The obtained inhibitory activity data against the <i>h</i>CA IX and XII isoforms showed that compound 7c was the most potent inhibitor in this sulphonyl thiourea series against enzyme <i>h</i>CA IX, with <i>K</i> _I = 125.1 ± 12.4 nM, while compound 7d was the most potent inhibitor against enzyme <i>h</i>CA XII, with <i>K</i> _I = 111.0 ± 12.3 nM. Compound 7c exhibited strong inhibitory activity among all four tested <i>h</i>CA enzymes, while thiourea 7f was a potent inhibitor for enzymes <i>h</i>CA I, II and XII. All these compounds demonstrated non-competitive inhibition of both enzymes. Some selected potential inhibitory compounds, including 7c, 7d, and 7g, exhibited remarkable cytotoxic activity against human cancer cell lines, including human breast adenocarcinoma (MCF-7), human liver adenocarcinoma (HepG2), human cervical epithelial carcinoma (HeLa), and human lung adenocarcinoma cells (A549). These compounds exhibited low cytotoxicity in the WI-38 cell line. The compounds 7c and 7d were the most potent inhibitors against tumour-associated <i>h</i>CA IX and <i>h</i>CA XII isoenzymes. Furthermore, these compounds exhibited remarkable inhibition against some cancer cell lines, such as MCF-7, HepG2, HeLa, and A549. They were subjected to <i>in silico</i> screening for molecular docking and molecular dynamics simulations. The results of <i>in vitro</i> and <i>in silico</i> studies revealed that compounds 7c and 7d were the most promising derivatives in this series owing to their significant effects on the studied <i>h</i>CA IX and <i>h</i>CA XII isoenzymes, respectively. The results showed that the sulphonyl thiourea moiety was deeply accommodated in the active site and interacted with zinc ions in the receptors.