DESIGN, SYNTHESIS, BIOACTIVITY AND MOLECULAR DOCKING OF IMIDAZOLONE DERIVATIVES HAVING HYDROPHILIC AND LIPOPHILIC FUNCTIONALITIES
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Date
2025-05-07
Authors
Fares, Oswa Marwan
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An-Najah National University
Abstract
The currently used chemotherapies showed negative side effects that can lead to permanent damage to human organs. Therefore, finding an effective anticancer therapy with minimum side effects is considered a major challenge for scientists. In this work, two new series of imidazolones were prepared, one containing phenyl group (3a-g) and the other containing thiophene group (5a-g). Both of these imidazolones were combined with different substituents including lipophilic and hydrophilic moieties. The synthesis was performed via condensation cyclization of vanillin-based oxazolones with various amines. The anticancer activity of the synthesized imidazolones was analyzed against four different cancer cell lines: liver cancer cells (HepG2), cervical adenocarcinoma cells (HeLa), colon cancer cells (CaCo-2) and breast cancer cells (MCF-7). Among the prepared imidazolones, it was found that imidazolone 3f with dodecyl chain exhibited the highest anticancer activity with IC50 value of 65.26 ± 3.2 µM against HepG2 and 20.02 ± 3.5 µM against MCF-7. Imidazolone 3d with amino alkyl group displayed an IC50 value of 36.57 ± 4.1 µM against the Hela cell and 24.68 ± 3.8 µM against the CaCo-2 cell line. Imidazolone 5g with thiophene and pyridyl group showed the highest efficiency among all tested derivatives with an IC50 value of 18.44 ± 2.3 µM and 5.96 ± 2.3 µM against Hela and CaCo-2 cell lines, respectively. Imidazolone 5b with chlorophenyl moiety displayed an IC50 value of 2.18 ± 0.7 µM and 5.51 ± 1.1 µM against HepG2 and Hela cell lines, respectively.
Computational tools were also used to evaluate the pharmacokinetics, and the antitumor potential of imidazolone molecules with the highest activities through ADME analysis and molecular docking. ADME properties, estimated by the Swiss ADME server, emphasize favorable drug-likeness under Lipinski’s guidelines, with molecular weights ranging from 357.43 (5d) to 468.65 g/mol (5f). Molecules 3g, 3f, 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 3g, 3f, 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 recognize 3g and 5f imidazolones as promising candidates for targeted cancer therapy.
In addition, antibacterial activity was studied for the prepared oxazolones. It was noticed that oxazolone 8 containing 2-thiophenyl moiety was the most potent to stop the bacterial growth of all types of bacteria, even the most resistant Staphylococcus aureus with MIC of 500 µg/mL. A combination of these oxazolones with commercial antibiotics can provide a synergetic effect to inhibit the bacterial growth at lower MIC values.