Design, synthesis, anticancer properties, and molecular docking of imidazolone derivatives with lipophilic moiety

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 (¹H and ¹³C 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 IC₅₀ 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 IC₅₀ 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 IC₅₀ 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 IC₅₀ 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.