Imidazolidin-4-one heterocycles belong to the broader imidazole family, a group of five-membered nitrogen-containing rings that medicinal chemists have prized since the first synthesis of imidazole by Debus in 1858 using glyoxal, ammonia, and formaldehyde. The imidazole scaffold appears in histidine and purine structures, giving it a natural capacity for molecular interactions with receptors and enzymes, and imidazole-containing molecules have been studied for antibacterial, antifungal, anti-inflammatory, antiviral, antiparasitic, and anticancer effects. What distinguishes the imidazolidin-4-one ring is the presence of a carbonyl group within the five-membered heterocycle, which contributes to both chemical reactivity and biological properties. The research team noted that most prior work on imidazole derivatives concentrated on experimental biological assessment, while relatively few studies combined synthesis, antibacterial evaluation, electronic structure analysis, drug-likeness prediction, and docking in a single investigation.

The synthetic route started from previously prepared hydrazone precursors, compounds F2 through F6, which contain the reactive azomethine carbon-nitrogen double bond. Equal moles of each hydrazone, 0.003 moles, were dissolved with the amino acid glycine, 0.075 grams, in 20 milliliters of absolute ethanol and heated for 15 hours. The proposed mechanism proceeds through nucleophilic addition of the amino group of glycine to the azomethine carbon of the hydrazone, followed by intramolecular cyclization and formation of the imidazolidin-4-one ring. After cooling and adding crushed ice, the precipitate was filtered and dried. The five products, F7 through F11, carry a shared 3-(bromomethyl)benzamide framework but differ in the para-substituent on the aromatic ring: bromo, chloro, nitro, methyl, and hydroxy groups respectively, giving each derivative a distinct electronic profile.

Spectroscopic evidence confirmed the cyclization at every step. In the Fourier-transform infrared spectra, recorded as potassium bromide pellets from 4000 to 400 inverse centimeters, the most significant change was the disappearance of the characteristic azomethine absorption band of the hydrazone precursors and the appearance of a new carbonyl band at 1649 to 1662 inverse centimeters, corresponding to the carbonyl of the imidazolidin-4-one heterocycle. Broad NH stretching zones appeared at 3165 to 3252 inverse centimeters, aromatic CH stretches at 3034 to 3078, and aliphatic CH stretches in two ranges, 2920 to 2962 and 2837 to 2912, indicating that the aromatic moieties had been retained while a new aliphatic heterocyclic environment had formed. Proton NMR spectra showed the loss of the azomethine proton signal and the emergence of ring NH protons at 6.78 to 6.51 parts per million, the characteristic ring CH proton at 6.35 to 5.30, and ring CH2 protons at 3.02 to 2.71, with amide NH protons at 10.01 to 9.19. Carbon-13 NMR confirmed the picture, with the azomethine carbon signal vanishing and the carbonyl carbon appearing at 167.56 to 162.64 parts per million. Elemental analysis for carbon, hydrogen, and nitrogen agreed with calculated values within plus or minus 0.4 percent, supporting the proposed molecular formulas. Yields ranged from 67 to 75 percent, and melting points spanned 197 to 237 degrees Celsius.

Antibacterial testing used the agar well diffusion method against both Gram-negative Escherichia coli and Gram-positive Staphylococcus aureus strains obtained from Tikrit University’s central laboratory. Muller-Hinton agar was prepared, sterilized at 120 degrees Celsius for 14 minutes under 1.5 bar of pressure, poured into Petri dishes, and swabbed with bacteria from three directions. Vehicle solutions of the compounds in DMSO were tested at three doses, 0.01, 0.001, and 0.0001 milligrams per milliliter, with ampicillin as the reference antibiotic. Inhibition zones correlated positively with concentration across the series, indicating concentration-dependent activity. Beyond the standout results for F9 against Staphylococcus aureus and F8 against Escherichia coli, the remaining compounds showed smaller zones: F7 reached 15 millimeters against Escherichia coli, F11 reached 12, and F10 reached 10. Ampicillin, however, produced larger zones against both organisms, 27 and 30 millimeters at the highest concentration, so the new derivatives remain active but do not yet outperform the established drug. The team attributed the differing responses of the two species to differences in cellular structure and suggested that the electronic and structural properties of the substituents likely shaped the activity differences, while acknowledging that agar well diffusion cannot reveal the exact mechanism of action and that establishing a structure-activity relationship would require further experimental research.

Density functional theory calculations, performed with Gaussian 09 at the B3LYP/6-311G(2d,2p) level after geometry optimization, probed the electronic behavior of the five derivatives. The computations yielded frontier molecular orbital energies and derived descriptors including chemical potential, chemical hardness, and the global electrophilicity index. Compound F9, bearing the electron-withdrawing nitro group, showed the lowest LUMO energy at minus 0.172145 Hartree, the lowest chemical hardness at 0.062183 Hartree, and the highest global electrophilicity index at 0.441518 Hartree, suggesting a comparatively greater theoretical tendency to accept electron density and higher electronic softness. Compound F11, containing the hydroxyl group, sat at the opposite pole with the highest chemical hardness, 0.101960 Hartree, and the lowest electrophilicity index, 0.216756 Hartree, indicating greater resistance to electronic deformation under the applied descriptors. Chemical potential values ranged from minus 0.234328 to minus 0.205320 Hartree, with F9 again the most negative. The authors stressed that these descriptors alone cannot establish antibacterial potency or predict minimum inhibitory concentrations, and that biological conclusions should rest primarily on the experimental results.

The SwissADME web server added a pharmacokinetic layer, estimating molecular weight, topological polar surface area, water solubility, skin permeability, rotatable bonds, and hydrogen bond donors and acceptors, with drug-likeness evaluated against Lipinski’s Rule of Five. Molecular weights fell between 388 and 453 grams per mole, all below the 500 threshold, and LogP values ranged from 1.54 to 2.77, indicating moderate lipophilicity. The halogenated compounds F7 and F8 posted the highest LogP values, 2.76 and 2.77, consistent with greater predicted permeability, while F9 had the lowest at 1.54. F9 also showed the highest topological polar surface area, 106.27 square angstroms, which the authors attributed to the higher molecular polarity caused by hydrogen-bonding functional groups in its structure, and it carried the most hydrogen bond acceptors at five. F11 was the most water-soluble by prediction, with a LogS of minus 3.62, while F7 was the least soluble at minus 4.67. Hydrogen bond donors varied from two to three. All compounds satisfied Lipinski criteria, but the authors cautioned that adherence to the rule does not mean biological activity, absorption, or drug candidacy, and that every SwissADME parameter is a theoretical estimate requiring experimental validation.

Molecular docking with AutoDock Vina examined the two most active compounds, F8 and F9, against biotin carboxylase from Escherichia coli, Protein Data Bank entry 3JZF, and biotin protein ligase from Staphylococcus aureus, entry 4DQ2, two enzymes central to bacterial metabolism and studied as prospective antibacterial targets. F8 docked to biotin carboxylase with an affinity of minus 6.3 kilocalories per mole, forming a hydrogen bond between the ring NH group and residue GLY:B:114 alongside van der Waals and pi-alkyl interactions. Against biotin protein ligase, F8 scored minus 5.6, with hydrogen bonds to SER:A:318 and additional contacts involving ASN:A:179, plus pi-pi stacked and pi-alkyl interactions. F9 matched F8’s minus 6.3 score at biotin carboxylase, hydrogen bonding to GLU:B:162, but delivered the strongest predicted interaction of the study at biotin protein ligase, minus 7.5 kilocalories per mole, with hydrogen bonds between HIS:A:126 and the NH group and between the carbonyl group and GLU:A:187, supplemented by pi-donor hydrogen bond, pi-pi stacking, pi-alkyl, and pi-sigma interactions. The docking pattern tracks the wet-lab results: F8 interacted more favorably with the Escherichia coli target, and F9 with the Staphylococcus aureus target.

The convergence of experimental and computational evidence gives this study an unusually complete picture of a new heterocyclic series at an early stage of development. The spectroscopic data cleanly verified the transformation of hydrazone precursors into the imidazolidin-4-one ring system, the agar diffusion assays identified the two most promising derivatives, and the docking scores offered a plausible molecular rationale for why F8 and F9 behaved differently against Gram-negative and Gram-positive organisms. Yet the authors were careful to flag the limits of their approach. The docking protocol was not validated by redocking the native co-crystallized ligand, so the deviation between predicted and crystallographic binding poses was never calculated. Docking scores are in-silico predictions that do not alone confirm enzyme inhibition or antibacterial mechanism, and the agar well diffusion method cannot determine the exact mode of action. The team concluded that the selected bacterial strains are sensitive to F8 and F9 and that the derivatives merit further investigation, but confirming the mechanism and biological relevance of the predicted interactions will require additional experimental verification, including work to establish the structure-activity relationship that the current data do not yet define.

Subject of Research: Synthesis, characterization, antibacterial activity, DFT analysis and molecular docking of new imidazolidin-4-one derivatives

Article Title: Synthesis, characterization, biological activity, density functional theory (DFT) and molecular docking of some new imidazolidin-4-one derivatives

Article References: Al-Badrany, K. A., Al-joboury, W. M. R., Homeda, Y. O., Saleh, J. N., Saleh, M. J., & Abdulmajeed, A. Z. (2026). Synthesis, characterization, biological activity, density functional theory (DFT) and molecular docking of some new imidazolidin-4-one derivatives. Results in Chemistry, 31, Article 103986. https://doi.org/10.1016/j.rechem.2026.103986

Image Credits: AI Generated

DOI: 10.1016/j.rechem.2026.103986

Keywords: imidazolidin-4-one, antibacterial, Staphylococcus aureus, Escherichia coli, density functional theory, molecular docking, SwissADME, hydrazone, drug-likeness, heterocycles, Synthesis, characterization