Department of Chemistry, Faculty of Arts and Science, Sakarya University, Sakarya, Turkey.
Department of Biochemistry, Faculty of Pharmacy, Erzincan Binali Yıldırım University, Erzincan, Turkey.
J Biomol Struct Dyn. 2024 Aug;42(12):6359-6377. doi: 10.1080/07391102.2023.2240889. Epub 2023 Aug 4.
In this study, a library of twelve beta-lactam-substituted benzenesulfonamides () was synthesized using the tail-approach method. The compounds were characterized using IR, H NMR, C NMR and elemental analysis techniques. These newly synthesized compounds were tested for their ability to inhibit the activity of two carbonic anhydrases (CA) isoforms, I and II, and acetylcholinesterase (AChE) . The results showed that the synthesized compounds were potent inhibitors of CA I, with s in the low nanomolar range (66.60-278.40 nM) than the reference drug acetazolamide (AAZ), which had a of 439.17 nM. The CA II was potently inhibited by compounds , and , with s of 69.56, 39.64, 79.63, 74.76, 78.93 and 74.94 nM, respectively (AAZ, of 98.28 nM). Notably, compound selectively inhibited CA II with a selectivity of > 4-fold over CA I. In terms of inhibition of AChE, the synthesized compounds had s ranging from 30.95 to 154.50 nM, compared to the reference drug tacrine, which had a of 159.61 nM. Compounds , and were also evaluated for their ability to inhibit the MCF-7 cancer cell line proliferation and were found to have promising anticancer activity, more potent than 5-fluorouracil and cisplatin. Molecular docking studies suggested that the sulfonamide moiety of these compounds fits snugly into the active sites of CAs and interacts with the Zn ion. Furthermore, molecular dynamics simulations were performed for 200 ns to assess the stability and dynamics of each enzyme-ligand complex. The acceptability of the compounds based on Lipinski's and Jorgensen's rules was also estimated from the ADME/T results. These results indicate that the synthesized molecules have the potential to be developed into effective and safe inhibitors of CAs and AChE and could be lead agents.Communicated by Ramaswamy H. Sarma.
在这项研究中，使用尾进法合成了 12 个β-内酰胺取代的苯磺酰胺（）库。通过 IR、H NMR、C NMR 和元素分析技术对化合物进行了表征。这些新合成的化合物被测试了它们抑制两种碳酸酐酶（CA）同工型 I 和 II 以及乙酰胆碱酯酶（AChE）的活性的能力。结果表明，合成的化合物是 CA I 的有效抑制剂，其在低纳摩尔范围内具有较高的抑制活性（66.60-278.40 nM），优于参考药物乙酰唑胺（AAZ），其抑制活性为 439.17 nM。CA II 被化合物、和强烈抑制，其抑制活性分别为 69.56、39.64、79.63、74.76、78.93 和 74.94 nM（AAZ 的抑制活性为 98.28 nM）。值得注意的是，化合物选择性地抑制 CA II，对 CA I 的选择性大于 4 倍。就 AChE 的抑制而言，合成的化合物的抑制活性范围为 30.95-154.50 nM，而参考药物他克林的抑制活性为 159.61 nM。化合物、和还评估了它们抑制 MCF-7 癌细胞系增殖的能力，发现它们具有有前途的抗癌活性，比 5-氟尿嘧啶和顺铂更有效。分子对接研究表明，这些化合物的磺酰胺部分适合 CA 的活性部位，并与 Zn 离子相互作用。此外，还进行了 200 ns 的分子动力学模拟，以评估每个酶-配体复合物的稳定性和动力学。根据 ADME/T 结果，还估计了化合物基于 Lipinski 和 Jorgensen 规则的可接受性。这些结果表明，合成的分子有可能被开发成有效的和安全的 CA 和 AChE 抑制剂，并且可能成为先导化合物。由 Ramaswamy H. Sarma 通讯。
