Fares Oswa, Hamed Othman, Assali Mohyeddin, Berisha Avni, Saadeh Haythem, Lail Bahia Abu, Dagdag Omar, Samaro Abdullah, Mansour Waseem, Jaradat Nidal, Abu-Jabal Saber
Department of Chemistry, Faculty of Science, An-Najah National University, P.O. Box 7, Nablus, Palestine.
Department of Pharmacy, Faculty of Medicine and Health Sciences, An-Najah National University, P.O. Box 7, Nablus, Palestine.
Sci Rep. 2025 May 27;15(1):18537. doi: 10.1038/s41598-025-97478-2.
As part of an ongoing investigation into imidazolone derivatives with anticancer activities, herein we present the synthesis of a new series of imidazolones with various substituents, including lipophilic and hydrophilic. All synthesized imidazolones (3a-3g and 5a-5g) were characterized by various spectroscopic methods (H and C NMR, FT-IR, and mass spectrometry). The preparation was performed by condensation cyclization of vanillin-based oxazolones with various amines. The anticancer efficiencies of the prepared imidazolones were tested against four different cancer cell lines liver cancer cells (HepG2), cervical adenocarcinoma cells (HeLa), colon cancer cells (CaCo-2), breast cancer cells (MCF-7). Among the prepared imidazolones the one with dodecyl chain displayed excellent efficiency against the tested cancer cell lines with an IC value of 65.3 ± 3.2 µM against HepG2 and 20.02 ± 3.5 µM against MCF-7. Imidazolone 2d with amino alkyl moiety displayed an IC value of 35.6 ± 4.1 µM against HeLa cell and 24.6 ± 3.8 µM against CaCo-2 cell line. Imidazolone 5g with thiophene and pyridyl group showed the highest activity among all tested derivatives with IC value of 18.6 ± 2.3 µM and 5.9 ± 2.3 µM against HeLa and CaCo-2 cell lines, respectively. Imidazolone 5b with a chlorophenyl moiety displayed an IC value of 2.2 ± 0.7 µM and 5.5 ± 1.1 µM against HepG2 and Hela cell lines, respectively. The study used computational tools to assess the pharmacokinetics and antitumor potential of the synthesized imidazolone molecules with the highest activities. They were evaluated through ADME analysis and molecular docking. ADME properties confirm favorable drug-likeness under Lipinski's guidelines, with molecular weights ranging from 357.43 (5d) to 468.65 g/mol (5f). Molecules 2g, 2f, and 5f show optimal hydrogen bonding, moderate bioavailability (0.55), and synthetic accessibility scores from 3.78 to 4.76. Docking studies with proteins 4MAN and 1HNJ highlight strong interactions for 2g, 2f, and 5f, with molecule 3g showing the best binding for 4MAN (- 52.13 kcal/mol) and 5f for 1HNJ (- 38.63 kcal/mol). These results identify 3g and 5f as promising candidates for targeted cancer therapy.
作为对具有抗癌活性的咪唑啉酮衍生物正在进行的研究的一部分，在此我们展示了一系列具有各种取代基（包括亲脂性和亲水性取代基）的新型咪唑啉酮的合成。所有合成的咪唑啉酮（3a - 3g和5a - 5g）均通过各种光谱方法（氢和碳核磁共振、傅里叶变换红外光谱和质谱）进行了表征。制备过程是通过香草醛基恶唑酮与各种胺的缩合环化反应来进行的。所制备的咪唑啉酮对四种不同癌细胞系进行了抗癌效率测试，即肝癌细胞（HepG2）、宫颈腺癌细胞（HeLa）、结肠癌细胞（CaCo - 2）、乳腺癌细胞（MCF - 7）。在所制备的咪唑啉酮中，具有十二烷基链的化合物对测试的癌细胞系表现出优异的效率，对HepG2的IC值为65.3±3.2 μM，对MCF - 7的IC值为20.02±3.5 μM。带有氨基烷基部分的咪唑啉酮2d对HeLa细胞的IC值为35.6±4.1 μM，对CaCo - 2细胞系的IC值为24.6±3.8 μM。带有噻吩和吡啶基的咪唑啉酮5g在所有测试衍生物中表现出最高活性，对HeLa和CaCo - 2细胞系的IC值分别为18.6±2.3 μM和5.9±2.3 μM。带有氯苯基部分的咪唑啉酮5b对HepG2和HeLa细胞系的IC值分别为2.2±0.7 μM和5.5±1.1 μM。该研究使用计算工具评估了具有最高活性的合成咪唑啉酮分子的药代动力学和抗肿瘤潜力。通过药物代谢动力学（ADME）分析和分子对接对它们进行了评估。ADME性质证实，根据Lipinski规则具有良好的类药物性质，分子量范围从357.43（5d）到468.65 g/mol（5f）。分子2g、2f和5f显示出最佳的氢键、适度的生物利用度（0.55）以及3.78至4.76的合成可及性得分。与蛋白质4MAN和1HNJ的对接研究突出了2g、2f和5f的强相互作用，分子3g对4MAN显示出最佳结合（-52.13 kcal/mol），5f对1HNJ显示出最佳结合（-38.63 kcal/mol）。这些结果确定3g和5f为靶向癌症治疗的有前景的候选物。
