Dinh Thanh Nguyen, Ngoc Toan Vu, Minh Trang Vu
Faculty of Chemistry, University of Science (Vietnam National University, Hanoi) 19 Le Thanh Tong, Hoan Kiem Ha Noi Vietnam
Institute of New Technology, Academy of Military Science and Technology, Ministry of Defence 17 Hoang Sam, Cau Giay Ha Noi Vietnam.
RSC Med Chem. 2024 Dec 11. doi: 10.1039/d4md00816b.
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.
使用一锅法设计并合成了一些含有4,6-二芳基嘧啶环的新型磺酰基硫脲衍生物（7a - m）。这些化合物对人碳酸酐酶CA I、CA II、CA IX和XII同工酶以及一些癌细胞系表现出显著的双重抑制活性。其中，一些硫脲对CA I同工酶的抑制活性顺序为7l > 7c > 7f，对CA II同工酶的抑制活性顺序为7f > 7b > 7c，对CA IX同工酶的抑制活性顺序为7c > 7g > 7a > 7b，对CA XII同工酶的抑制活性顺序为7d > 7c > 7g > 7f，具有显著更强的抑制活性。所获得的针对CA IX和XII同工酶的抑制活性数据表明，化合物7c是该磺酰基硫脲系列中对酶CA IX最有效的抑制剂，IC₅₀ = 125.1 ± 12.4 nM，而化合物7d是对酶CA XII最有效的抑制剂，IC₅₀ = 111.0 ± 12.3 nM。化合物7c在所有四种测试的CA酶中均表现出强抑制活性，而硫脲7f是酶CA I、II和XII的有效抑制剂。所有这些化合物对两种酶均表现出非竞争性抑制。一些选定的潜在抑制性化合物，包括7c、7d和7g，对人癌细胞系，包括人乳腺腺癌（MCF - 7）、人肝腺癌（HepG2）、人宫颈上皮癌（HeLa）和人肺腺癌细胞（A549）表现出显著的细胞毒性活性。这些化合物在WI - 38细胞系中表现出低细胞毒性。化合物7c和7d是针对肿瘤相关CA IX和CA XII同工酶的最有效抑制剂。此外，这些化合物对一些癌细胞系，如MCF - 7、HepG2、HeLa和A549表现出显著的抑制作用。它们接受了分子对接和分子动力学模拟筛选。分子对接和分子动力学模拟研究结果表明，化合物7c和7d分别因其对所研究的CA IX和CA XII同工酶的显著作用，是该系列中最有前景的衍生物。结果表明，磺酰基硫脲部分深深地容纳在活性位点并与受体中的锌离子相互作用。
