Sulphonyl thiourea compounds containing pyrimidine as dual inhibitors of I, II, IX, and XII carbonic anhydrases and cancer cell lines: synthesis, characterization and 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 CA I, CA II, 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 CA I isoform), 7f > 7b > 7c (against the CA II isoform), 7c > 7g > 7a > 7b (against the CA IX isoform), and 7d > 7c > 7g > 7f (against the CA XII isoform). The obtained inhibitory activity data against the CA IX and XII isoforms showed that compound 7c was the most potent inhibitor in this sulphonyl thiourea series against enzyme CA IX, with = 125.1 ± 12.4 nM, while compound 7d was the most potent inhibitor against enzyme CA XII, with = 111.0 ± 12.3 nM. Compound 7c exhibited strong inhibitory activity among all four tested CA enzymes, while thiourea 7f was a potent inhibitor for enzymes 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 CA IX and 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 screening for molecular docking and molecular dynamics simulations. The results of and studies revealed that compounds 7c and 7d were the most promising derivatives in this series owing to their significant effects on the studied CA IX and 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.