Synthesis, Structure, and Stability of Copper(II) Complexes Containing Imidazoline-Phthalazine Ligands with Potential Anticancer Activity
Abstract
:1. Introduction
2. Results and Discussion
2.1. Chemistry
Synthesis of Dichloro[2-(4,5-dihydro-1H-imidazol-2-yl)phthalazin-1(2H)-imine]copper(II) (C1) and Dichloro[2-(1-benzoyl-4,5-dihydro-1H-imidazol-2-yl)phthalazin-1(2H)-one]copper(II) (C2)
2.2. Structure of Copper(II) Complexes C1 and C2
Crystallographic Studies of Ligand L3 and Copper(II) Complex C2
2.3. Stability of Copper(II) Complexes—UV-Vis Investigations of Compounds C1 and C2 in Phosphate-Buffered Saline Solution (PBS)
2.4. In Silico Molecular Modeling of Ligand L3
2.5. In Vitro Anticancer Potential
2.6. Antimicrobial Activity
2.7. Determination of Antioxidant Activity
2.8. In Silico Physicochemical, Pharmacokinetic, and Drug-Likeness Predictions for Ligands L1 and L3 and Cu(II) Complexes C1 and C2
3. Materials and Methods
3.1. Experimental Part
3.1.1. General Information
3.1.2. Preparation of Free Ligands: N-(2-(1-Benzoyl-4,5-dihydro-1H-imidazol-2-yl)phthalazin-1(2H)-ylidene)benzamide (L2) and 2-(1-Benzoyl-4,5-dihydro-1H-imidazol-2-yl)phthalazin-1(2H)-one (L3)
First Step—Synthesis of Ligand L2 and Its Purification
Second Step—Synthesis of Ligand L3
3.1.3. Synthesis of Copper(II) Complexes C1 and C2
Synthesis of Dichloro[2-(4,5-dihydro-1H-imidazol-2-yl)phthalazin-1(2H)-imine]copper(II) (C1)
Synthesis of Dichloro[2-(1-benzoyl-4,5-dihydro-1H-imidazol-2-yl)phthalazin-1(2H)-one]copper(II) (C2)
3.2. Stability Studies of Dichloro[2-(4,5-dihydro-1H-imidazol-2-yl)phthalazin-1(2H)-imine]copper(II) (C1) and Dichloro[2-(1-benzoyl-4,5-dihydro-1H-imidazol-2-yl)phthalazin-1(2H)-one]copper(II) (C2)
3.3. Biology
3.3.1. Evaluation of In Vitro Cytotoxicity
Cell Culture
The MTT Assay
Statistical Analysis
3.3.2. Determination of Minimum Inhibitory Concentration (MIC) and Minimum Bactericidal/Fungicidal Concentration (MBC/MFC)
3.3.3. Antioxidant Studies
Materials
DPPH Radical Scavenging Assay
ABTS Radical Scavenging Assay
FRAP Test
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 Reference | L3 | C2 |
---|---|---|
Chemical formula | C18H14N4O2 | C18H14N4O2Cl2Cu |
Formula mass | 318.33 | 452.77 |
Crystal system | triclinic | triclinic |
a/Å | 8.3830(3) | 7.38342(18) |
b/Å | 8.7581(2) | 10.0507(3) |
c/Å | 10.8035(3) | 12.8296(3) |
α/° | 102.174(3) | 91.220(2) |
β° | 102.877(3) | 91.9414(18) |
ɣ° | 91.121(2) | 110.026(2) |
Unit cell volume/Å3 | 754.00(4) | 893.44(4) |
Space group | P-1 | P-1 |
Z | 2 | 2 |
Radiation type | Mo Kα | Cu Kα |
Absorption coefficient, μ/mm−1 | 0.095 | 4.673 |
No. of refl. measured, 2Θmax/° | 20,402, 52.7 | 22,327, 153.1 |
No. of independent reflections | 3074 | 3714 |
Rint | 0.0182 | 0.0276 |
Final R1 values (I > 2σ(I)) | 0.0402 | 0.0266 |
Final wR(F2) values (I > 2σ(I)) | 0.0906 | 0.0734 |
Final R1 values (all data) | 0.0453 | 0.0285 |
Final wR(F2) values (all data) | 0.1008 | 0.0751 |
Goodness of fit on F2 | 1.037 | 1.059 |
Compound Reference | L3 | C2 |
---|---|---|
dO···C (Å) | 2.9547(17) | 2.655(2) |
ΘO···C=O (°) | 114.31(10) | 113.42(13) |
TC=O···C=O (°) | 169.83(12) | 169.82(16) |
Compound Reference | L3 | C2 |
---|---|---|
Bond lengths (Å) | ||
C1-O16 | 1.2057(16) | 1.209(2) |
C1-N2 | 1.3846(17) | 1.417(2) |
N2-N3 | 1.3966(16) | 1.4006(18) |
N2-C11 | 1.4142(17) | 1.397(2) |
C11-N15 | 1.2612(18) | 1.283(2) |
C11-N12 | 1.3963(17) | 1.367(2) |
N12-C17 | 1.3788(18) | 1.408(2) |
C17-O18 | 1.2146(16) | 1.207(2) |
Cu1-Cl1 | 2.2262(5) | |
Cu1-Cl2 | 2.2420(5) | |
Cu1-N3 | 2.0844(13) | |
Cu1-N15 | 1.9634(15) | |
Bond angles (°) | ||
C4 N3 N2 | 115.31(11) | 118.03(13) |
C11 N15 C14 | 105.60(12) | 107.55(14) |
C11 N2 C1 | 119.15(11) | 123.44(13) |
N12 C11 N2 | 120.63(11) | 125.00(14) |
C11 N12 C17 | 131.66(11) | 133.28(14) |
Torsion angles (°) | ||
N3 N2 C11 N15 | 55.60(18) | 14.3(2) |
C11 N12 C17 C19 | 36.1(2) | 30.4(3) |
N12 C17 C19 C24 | 37.58(19) | 24.7(2) |
HeLa Cell Line | ||||||
---|---|---|---|---|---|---|
Conc. [μg/mL] | 1 | 10 | 25 | 50 | 100 | 200 |
Compound | Mean % of Control | |||||
L1 | 100 | 94.5 | 91.8 | 79.3 | 58.1 | 34.1 |
C1 | 97.3 | 97.1 | 97.4 | 93.9 | 91.0 | 56.4 |
L3 | 96.5 | 92.1 | 92.4 | 94.8 | 94.1 | 86.4 |
C2 | 99.9 | 97.5 | 93.3 | 95.2 | 77.7 | 18.8 |
Cisplatin* | 93.1 | 90.3 | 80.6 | 72.3 | 5.0 | 2.5 |
MCF-7 Cell Line | ||||||
---|---|---|---|---|---|---|
Conc. [μg/mL] | 1 | 10 | 25 | 50 | 100 | 200 |
Compound | Mean % of Control | |||||
L1 | 97.3 | 97.2 | 93.7 | 86.4 | 62.1 | 45.7 |
C1 | 100 | 100 | 100 | 97.9 | 86.2 | 49.2 |
L3 | 95.9 | 100 | 97.2 | 99.4 | 96.5 | 95.6 |
C2 | 100 | 100 | 96.4 | 92.5 | 73.7 | 42.5 |
Cisplatin* | 100 | 96.4 | 81.9 | 64.1 | 18.8 | 6.5 |
MDA-MB-231 Cell Line | ||||||
---|---|---|---|---|---|---|
Conc. [μg/mL] | 1 | 10 | 25 | 50 | 100 | 200 |
Compound | Mean % of Control | |||||
L1 | 99.3 | 97.8 | 95.0 | 81.4 | 52.7 | 35.2 |
C1 | 90.5 | 88.8 | 89.6 | 81.7 | 80.5 | 18.7 |
L3 | 97.2 | 97.6 | 96.6 | 94.9 | 96.2 | 96.7 |
C2 | 96.2 | 97.5 | 93.5 | 88.9 | 70.5 | 23.6 |
Cisplatin* | 98.2 | 87.7 | 82.4 | 57.6 | 31.9 | 22.6 |
HDFa Cell Line | |||
---|---|---|---|
Conc. [μg/mL] | 50 | 100 | 200 |
Compound | Mean % of Control | ||
L1 | 85.6 | 81.3 | 84.8 |
C1 | - | 86.9 | 75.6 |
C2 | - | 78.8 | 68.1 |
Cisplatin* | 76.8 | 26.8 | 4.1 |
Compound | ABTS | DPPH | FRAP |
---|---|---|---|
L1 | 23.63 ± 0.28 | 197.89 ± 1.79 | NR * |
L3 | 198.66 ± 1.33 | 427.34 ± 2.25 | 214.28 ± 0.2 |
C1 | 253.92 ± 2.15 | 63.35 ± 0.25 | 156.01 ± 0.35 |
C2 | 400.37 ± 0.87 | 78.33 ± 1.13 | 158.32 ± 0.21 |
Ascorbic acid | 15.68 ± 0.8 | 12.75 ± 0.55 | 10.17 ± 0.51 |
Physicochemical Properties | Lipophilicity | Water Sol. | Pharmacokinetics | Drug-Likeness | ||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
Mol. Wt. | ROTB (n) | HBA (n) | HBD (n) | TPSA | CLogP | Solubility Class | GI abs. | BBB perm. | CYP1A2 * | CYP2C19 * | Lipinski Filter | |
Rule | <500 | <10 | <10 | <5 | - | <5 | - | - | - | - | - | - |
L1 | 213.24 | 1 | 3 | 2 | 66.06 | 1.07 | soluble (v) | high | No | Yes | No | Yes(0) |
L3 | 318.33 | 3 | 4 | 0 | 59.60 | 2.17 | soluble | high | No | Yes | Yes | Yes(0) |
C1 | 347.69 | 1 | 3 | 2 | 66.05 | 1.41 | soluble | high | No | Yes | No | Yes(0) |
C2 | 452.78 | 3 | 4 | 0 | 67.56 | 2.39 | soluble (m) | high | Yes | Yes | No | Yes(0) |
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Balewski, Ł.; Inkielewicz-Stępniak, I.; Gdaniec, M.; Turecka, K.; Hering, A.; Ordyszewska, A.; Kornicka, A. Synthesis, Structure, and Stability of Copper(II) Complexes Containing Imidazoline-Phthalazine Ligands with Potential Anticancer Activity. Pharmaceuticals 2025, 18, 375. https://doi.org/10.3390/ph18030375
Balewski Ł, Inkielewicz-Stępniak I, Gdaniec M, Turecka K, Hering A, Ordyszewska A, Kornicka A. Synthesis, Structure, and Stability of Copper(II) Complexes Containing Imidazoline-Phthalazine Ligands with Potential Anticancer Activity. Pharmaceuticals. 2025; 18(3):375. https://doi.org/10.3390/ph18030375
Chicago/Turabian StyleBalewski, Łukasz, Iwona Inkielewicz-Stępniak, Maria Gdaniec, Katarzyna Turecka, Anna Hering, Anna Ordyszewska, and Anita Kornicka. 2025. "Synthesis, Structure, and Stability of Copper(II) Complexes Containing Imidazoline-Phthalazine Ligands with Potential Anticancer Activity" Pharmaceuticals 18, no. 3: 375. https://doi.org/10.3390/ph18030375
APA StyleBalewski, Ł., Inkielewicz-Stępniak, I., Gdaniec, M., Turecka, K., Hering, A., Ordyszewska, A., & Kornicka, A. (2025). Synthesis, Structure, and Stability of Copper(II) Complexes Containing Imidazoline-Phthalazine Ligands with Potential Anticancer Activity. Pharmaceuticals, 18(3), 375. https://doi.org/10.3390/ph18030375