Synthesis, Antitumor Activities, and Apoptosis-Inducing Activities of Schiff’s Bases Incorporating Imidazolidine-2,4-dione Scaffold: Molecular Docking Studies and Enzymatic Inhibition Activities
Abstract
:1. Introduction
2. Results and Discussion
2.1. Chemistry
2.2. In Vitro Cytotoxicity Assay and SAR Study
2.3. In Vitro Cytotoxicity Against Normal Human Cells (WI-38)
2.4. Kinase Inhibition Activity
2.5. Measuring the Expression of Anti-Apoptotic Proteins (MCL-1 and BCL-2) in MCF-7 Cells
2.6. Cell Cycle Arrest Analysis
2.7. Drug Likeness
2.8. ADMET Properties
2.9. Molecular Docking Studies
2.9.1. Validation of Docking Approach
2.9.2. Molecular Docking
Docking of Compound 24 into HER2
Docking Other Derivatives into HER2
Docking of Compound 24 into EGFR
Docking Other Derivatives into EGFR
2.9.3. Molecular Dynamics (MD) Simulation
Root Mean Square Deviation (RMSD)
Root Mean Square Fluctuation (RMSF)
Compactness
3. Materials and Methods
3.1. General
3.1.1. General Procedure for the Synthesis of Compounds 7–27
2-(2,5-Dioxo-4,4-diphenylimidazolidin-1-yl)-N′-(1-phenylethylidene)acetohydrazide (7)
2-(2,5-Dioxo-4,4-diphenylimidazolidin-1-yl)-N′-(1-(o-tolyl)ethylidene)acetohydrazide (8)
2-(2,5-Dioxo-4,4-diphenylimidazolidin-1-yl)-N′-(1-(p-tolyl)ethylidene)acetohydrazide (9)
N′-(1-(4-Chlorophenyl)ethylidene)-2-(2,5-dioxo-4,4-diphenylimidazolidin-1-yl)acetohydrazide (10)
2-(2,5-Dioxo-4,4-diphenylimidazolidin-1-yl)-N′-(1-(4-fluorophenyl)ethylidene)acetohydrazide (11)
2-(2,5-Dioxo-4,4-diphenylimidazolidin-1-yl)-N′-(1-(4-(trifluoromethyl)phenyl)ethylidene)acetohydrazide (12)
2-(2,5-Dioxo-4,4-diphenylimidazolidin-1-yl)-N′-(1-(4-(trifluoromethoxy)phenyl)ethylidene)acetohydrazide (13)
2-(2,5-Dioxo-4,4-diphenylimidazolidin-1-yl)-N′-(1-(2-methoxyphenyl)ethylidene)acetohydrazide (14)
2-(2,5-Dioxo-4,4-diphenylimidazolidin-1-yl)-N′-(1-(3-methoxyphenyl)ethylidene)acetohydrazide (15)
2-(2,5-Dioxo-4,4-diphenylimidazolidin-1-yl)-N′-(1-(4-methoxyphenyl)ethylidene)acetohydrazide (16)
N′-(1-(3,4-Dimethoxyphenyl)ethylidene)-2-(2,5-dioxo-4,4-diphenylimidazolidin-1-yl)acetohydrazide (17)
2-(2,5-Dioxo-4,4-diphenylimidazolidin-1-yl)-N′-(1-(3,4,5-trimethoxyphenyl)ethylidene)acetohydrazide (18)
2-(2,5-Dioxo-4,4-diphenylimidazolidin-1-yl)-N′-(1-(4-nitrophenyl)ethylidene)acetohydrazide (19)
2-(2,5-Dioxo-4,4-diphenylimidazolidin-1-yl)-N′-(1-(pyridin-2-yl)ethylidene)acetohydrazide (20)
2-(2,5-Dioxo-4,4-diphenylimidazolidin-1-yl)-N′-(1-(pyridin-3-yl)ethylidene)acetohydrazide (21)
2-(2,5-Dioxo-4,4-diphenylimidazolidin-1-yl)-N′-(1-(pyridin-4-yl)ethylidene)acetohydrazide (22)
2-(2,5-Dioxo-4,4-diphenylimidazolidin-1-yl)-N′-(1-(naphthalen-1-yl)ethylidene)acetohydrazide (23)
2-(2,5-Dioxo-4,4-diphenylimidazolidin-1-yl)-N′-(1-(naphthalen-2-yl)ethylidene)acetohydrazide (24)
2-(2,5-Dioxo-4,4-diphenylimidazolidin-1-yl)-N′-(1-(furan-2-yl)ethylidene)acetohydrazide (25)
2-(2,5-Dioxo-4,4-diphenylimidazolidin-1-yl)-N′-(1-(thiophen-2-yl)ethylidene)acetohydrazide (26)
N′-(1-(5-Chlorothiophen-2-yl)ethylidene)-2-(2,5-dioxo-4,4-diphenylimidazolidin-1-yl)acetohydrazide (27)
3.2. Biological Activity
3.2.1. In Vitro Cytotoxicity Assay
3.2.2. In Vitro Kinase Inhibition Assay
3.2.3. Apoptosis Assay
3.2.4. Cell Cycle Analysis
3.3. Molecular Docking Methodology of the Selected Compound
3.3.1. Protein Selection and Preparation
3.3.2. Compound and Reference Inhibitor Preparation
3.3.3. Docking Process
3.3.4. MD Simulation Studies
3.4. ADMET Prediction
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Compound | Ar | IC50 (μM) a | ||
---|---|---|---|---|
HCT-116 | HePG-2 | MCF-7 | ||
7 | Ph | 47.46 ± 2.8 | 55.81 ± 3.3 | 38.30 ± 2.2 |
8 | 2-CH3-Ph | 37.61 ± 2.3 | 25.43 ± 1.8 | 34.06 ± 2.0 |
9 | 4-CH3-Ph | 71.23 ± 3.8 | 29.73 ± 2.1 | 69.01 ± 3.9 |
10 | 4-Cl-Ph | 17.90 ± 1.4 | 10.69 ± 0.9 | 11.18 ± 0.9 |
11 | 4-F-Ph | 28.33 ± 2.1 | 21.06 ± 1.8 | 14.25 ± 1.2 |
12 | 4-CF3-Ph | 52.48 ± 3.0 | 47.71 ± 2.7 | 45.83 ± 2.4 |
13 | 4-OCF3-Ph | 20.11 ± 1.7 | 13.94 ± 1.2 | 9.58 ± 0.8 |
14 | 2-OCH3-Ph | 74.03 ± 3.9 | 63.27 ± 3.8 | 59.14 ± 3.4 |
15 | 3-OCH3-Ph | 53.85 ± 3.1 | 45.12 ± 2.5 | 55.33 ± 3.2 |
16 | 4-OCH3-Ph | 36.52 ± 2.4 | 27.28 ± 2.0 | 35.82 ± 2.1 |
17 | 3,4-Di-OCH3-Ph | 26.75 ± 2.0 | 19.63 ± 1.7 | 15.71 ± 1.3 |
18 | 3,4,5-Tri-OCH3-Ph | 39.63 ± 2.4 | 37.24 ± 2.3 | 26.02 ± 1.6 |
19 | 4-NO2-Ph | 31.27 ± 2.1 | 19.90 ± 1.8 | 20.42 ± 1.5 |
20 | 2-Pyridyl | 46.72 ± 2.7 | 49.10 ± 2.8 | 32.39 ± 1.9 |
21 | 3-Pyridyl | 19.25 ± 1.5 | 11.50 ± 1.0 | 8.61 ± 0.6 |
22 | 4-Pyridyl | 25.96 ± 1.9 | 17.18 ± 1.6 | 13.11 ± 1.1 |
23 | 1-Naphthyl | 34.39 ± 2.3 | 31.82 ± 2.1 | 28.13 ± 1.7 |
24 | 2-Naphthyl | 12.83 ± 0.9 | 9.07 ± 0.8 | 4.92 ± 0.3 |
25 | 2-Furyl | 49.94 ± 2.9 | 34.56 ± 2.1 | 47.28 ± 2.6 |
26 | 2-Thiophenyl | 87.50 ± 4.6 | 32.26 ± 2.2 | 76.83 ± 4.2 |
27 | 5-Cl-2-thiophenyl | 33.18 ± 2.2 | 16.84 ± 1.6 | 19.72 ± 1.5 |
Doxorubicin | - | 5.23 ± 0.3 | 4.50 ± 0.2 | 4.17 ± 0.2 |
Erlotinib | - | 8.53 ± 0.5 | 7.90 ± 0.6 | 5.18 ± 0.4 |
Comp. | WI-38 | MCF-7 | *SI | HCT-116 | SI | HePG-2 | SI |
---|---|---|---|---|---|---|---|
10 | 54.21 | 11.18 | 4.84 | 17.9 | 3.02 | 10.69 | 5.07 |
13 | 45.39 | 9.58 | 4.73 | 20.11 | 2.25 | 13.94 | 3.25 |
21 | 60.79 | 8.61 | 7.06 | 19.25 | 3.15 | 11.5 | 5.28 |
24 | 39.52 | 4.92 | 8.03 | 12.83 | 3.08 | 9.07 | 4.35 |
Doxorubicin | 6.72 | 4.17 | 1.61 | 5.23 | 1.28 | 4.5 | 1.49 |
Erlotinib | 46.52 | 5.18 | 8.98 | 8.53 | 5.45 | 7.9 | 5.88 |
Compound | Ar | Kinase Inhibition IC50 (µM) | |
---|---|---|---|
EGFR | HER2 | ||
10 | 4-ChloroPh | 0.67 ± 0.03 | 0.71 ± 0.02 |
13 | 4-TrifluoromethoxyPh | 0.61 ± 0.02 | 0.28 ± 0.01 |
21 | 3-Pyridyl | 1.61 ± 0.07 | 1.17 ± 0.04 |
24 | 2-Naphthyl | 0.07 ± 0.004 | 0.04 ± 0.001 |
Erlotinib | - | 0.05 ± 0.002 | nt |
Lapatinib | - | nt | 0.03 ± 0.001 |
Concentrations | %G0–G1 | %S | %G2/M | Comment |
---|---|---|---|---|
24 at 2 µM | 52.12 | 22.45 | 25.43 | Cell cycle arrest at G2/M |
24 at 10 µM | 50.61 | 15.93 | 33.46 | - |
Erlotinib at 2 µM | 46.12 | 22.83 | 31.05 | Cell cycle arrest at G2/M |
Erlotinib at 10 µM | 35.89 | 15.72 | 48.39 | - |
Cont. MCF-7 | 63.19 | 28.99 | 7.82 | - |
Compound | Ligand | Receptor | Interaction | Distance (Å) | E (kcal/mol) | S (kcal/mol) |
---|---|---|---|---|---|---|
The HER2 kinase domain (PDB code: 3PP0) | ||||||
Comp. 24 | N 26 | O Leu 726 (A) | H-donor | 2.85 | −1.9 | −8.78 |
C 29 | O Arg849 (A) | H-donor | 3.44 | −0.7 | ||
N 35 | N Asp863 (A) | H-acceptor | 3.3 | −1.1 | ||
O 58 | CA Asn850 (A) | H-acceptor | 3.56 | −0.3 | ||
6-ring | N Cys805 (A) | pi-H | 3.47 | −0.5 | ||
6-ring | CD2 Leu852 (A) | pi-H | 3.76 | −0.3 | ||
6-ring | CB Phe864 (A) | pi-H | 4.94 | −0.3 | ||
6-ring | CD2 Phe864 (A) | pi-H | 4.27 | −0.5 | ||
03Q | O1 1 | OD2 Asp863 (A) | H-donor | 3.03 | −2 | −10.68 |
C12 23 | O Gln799 (A) | H-donor | 3.27 | −0.4 | ||
CL32 50 | O Leu796 (A) | H-donor | 3.21 | −0.3 | ||
N11 22 | N Met801 (A) | H-acceptor | 2.9 | −5.5 | ||
N18 32 | CA Asp863 (A) | H-acceptor | 3.19 | −1.3 | ||
6-ring | CD1 Leu785 (A) | pi-H | 4.3 | −0.4 | ||
6-ring | CD1 Leu800 (A) | pi-H | 4.7 | −0.4 | ||
6-ring | CD1 Leu852 (A) | pi-H | 3.42 | −0.4 | ||
6-ring | CD2 Phe864 (A) | pi-H | 3.83 | −0.3 | ||
The EGFR kinase domain (PDB code: 2ITY) | ||||||
Comp. 24 | O 58 | N Met793 (A) | H-acceptor | 3.14 | −2.3 | −6.71 |
6-ring | N Asp855 (A) | pi-H | 4.32 | −0.5 | ||
IRE | C2 20 | O Gln791 (A) | H-donor | 3.42 | −0.5 | −6.53 |
N3 19 | N Met793 (A) | H-acceptor | 2.67 | −4.7 | ||
6-ring | CD1 Leu718 (A) | pi-H | 4.17 | −0.5 | ||
6-ring | CD Lys745 (A) | pi-H | 4.31 | −0.5 | ||
6-ring | CD1 Leu792 (A) | pi-H | 4.97 | −0.3 |
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Alanazi, F.S.; Alkahtani, H.M.; Abdel-Aziz, A.A.-M.; El-Azab, A.S.; Asiri, H.H.; Bakheit, A.H.; Al-Omary, F.A. Synthesis, Antitumor Activities, and Apoptosis-Inducing Activities of Schiff’s Bases Incorporating Imidazolidine-2,4-dione Scaffold: Molecular Docking Studies and Enzymatic Inhibition Activities. Pharmaceuticals 2025, 18, 496. https://doi.org/10.3390/ph18040496
Alanazi FS, Alkahtani HM, Abdel-Aziz AA-M, El-Azab AS, Asiri HH, Bakheit AH, Al-Omary FA. Synthesis, Antitumor Activities, and Apoptosis-Inducing Activities of Schiff’s Bases Incorporating Imidazolidine-2,4-dione Scaffold: Molecular Docking Studies and Enzymatic Inhibition Activities. Pharmaceuticals. 2025; 18(4):496. https://doi.org/10.3390/ph18040496
Chicago/Turabian StyleAlanazi, Fhdah S., Hamad M. Alkahtani, Alaa A.-M. Abdel-Aziz, Adel S. El-Azab, Hanadi H. Asiri, Ahmed H. Bakheit, and Fatmah A. Al-Omary. 2025. "Synthesis, Antitumor Activities, and Apoptosis-Inducing Activities of Schiff’s Bases Incorporating Imidazolidine-2,4-dione Scaffold: Molecular Docking Studies and Enzymatic Inhibition Activities" Pharmaceuticals 18, no. 4: 496. https://doi.org/10.3390/ph18040496
APA StyleAlanazi, F. S., Alkahtani, H. M., Abdel-Aziz, A. A.-M., El-Azab, A. S., Asiri, H. H., Bakheit, A. H., & Al-Omary, F. A. (2025). Synthesis, Antitumor Activities, and Apoptosis-Inducing Activities of Schiff’s Bases Incorporating Imidazolidine-2,4-dione Scaffold: Molecular Docking Studies and Enzymatic Inhibition Activities. Pharmaceuticals, 18(4), 496. https://doi.org/10.3390/ph18040496