Copper(II) Complexes with 1-(Isoquinolin-3-yl)heteroalkyl-2-ones: Synthesis, Structure and Evaluation of Anticancer, Antimicrobial and Antioxidant Potential
Abstract
:1. Introduction
2. Results and Discussion
2.1. Chemistry
2.1.1. Synthesis of 1-(Isoquinolin-3-yl)heteroalkyl-2-one Ligands L1–4
2.1.2. Synthesis of Copper(II) Complexes of 1-(Isoquinolin-3-yl)heteroalkyl-2-ones C1–4
2.2. Structural Analysis of Copper(II) Complexes C1–4
2.2.1. Infrared Spectra
2.2.2. X-ray Crystallographic Studies
2.2.3. Molecular Modeling Studies of Ligands L1 and L2
2.3. Stability Studies of Copper(II) Complexes C1–4 in Aqueous Buffer
2.4. Biological Evaluation
2.4.1. In Vitro Cytotoxic Activity
2.4.2. Cell Cycle Analysis
2.4.3. Interaction of Copper(II) Complex C2 with Clinically Used Anticancer Agents
2.4.4. Antimicrobial Activity
2.5. Determination of Free Radical Scavenging Capacity
2.6. In Silico Physicochemical, Pharmacokinetic and Drug-Likeness Predictions
3. Materials and Methods
3.1. Chemistry
3.1.1. General Information
3.1.2. Synthesis of 1-(Isoquinolin-3-yl)imidazolidin-2-one (L2)
3.1.3. Synthesis of 1-Ethyl-3-(isoquinolin-3-yl)imidazolidin-2-one (L4)
3.1.4. Synthesis of Copper(II) Complexes of 1-(Isoquinolin-3-yl)heteroalkyl-2-ones C1–4 (General Method)
Dichloro{bis[1-(Isoquinolin-3-yl)azetidin-2-one]}copper(II) (C1)
Dichloro{bis[1-(Isoquinolin-3-yl)imidazolidin-2-one]}copper(II) (C2)
Dichloro[1-(Isoquinolin-3-yl)-3-methylimidazolidin-2-one]copper(II) (C3)
Dichloro[1-ethyl-3-(isoquinolin-3-yl)imidazolidin-2-one]copper(II) (C4)
3.1.5. Single Crystal X-ray Diffraction Studies
3.2. Aqueous Stability Studies
3.3. Biological Studies
3.3.1. Examination of the Cytotoxic Activity with Assessment by MTT Assay
3.3.2. Cell Cycle Analysis
3.3.3. Analysis of Interaction of Copper(II) Complex C2 (CX) with Clinically Used Anticancer Agents
3.3.4. In Vitro Antimicrobial Activity
3.4. Antioxidant
3.4.1. Materials
3.4.2. DPPH Assay
3.4.3. ABTS Assay
3.5. ADME/Drug-Likeness Calculation
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 | (C1_1_auto) |
---|---|
Chemical formula | C24H20Cl2CuN4O2 |
Mr | 530.89 |
Crystal system, space group | Triclinic, |
Temperature (K) | 100 |
a, b, c (Å) | 7.8288 (2), 8.2173 (2), 9.5081 (2) |
α, β, γ (°) | 106.092 (2), 111.334 (3), 97.897 (2) |
V (Å3) | 527.68 (2) |
Z | 1 |
Radiation type | Mo Kα |
μ (mm−1) | 1.32 |
Crystal size (mm) | 0.22 × 0.2 × 0.09 |
Diffractometer | XtaLAB Synergy, Dualflex, Pilatus 300 K |
Tmin, Tmax | 0.586, 1.000 |
No. of measured, independent and observed [I > 2σ(I)] reflections | 15,833, 3057, 2752 |
Rint | 0.040 |
(sin θ/λ)max (Å−1) | 0.748 |
R[F2 > 2σ(F2)], wR(F2), S | 0.029, 0.072, 1.09 |
No. of reflections | 3057 |
No. of parameters | 151 |
H-atom treatment | H-atom parameters constrained |
Δmax, Δmin (e Å−3) | 0.91, −0.35 |
D—H···A | D—H (Å) | H⋯A (Å) | D···A (Å) | D—H⋯A (º) |
---|---|---|---|---|
C9—H9···Cl1 i | 0.95 | 2.86 | 3.7205 (15) | 152 |
C2—H2···O1 ii | 0.95 | 2.21 | 2.9512 (19) | 135 |
Ligands/Complexes | IC50 ± SD (μg/mL) | ||||
---|---|---|---|---|---|
Cell Line | |||||
A375 | HepG2 | LS180 | T98G | CCD-1059-Sk | |
L1 | >200 | >200 | >200 | >200 | >200 |
C1 | 37.97 ± 3.01 | 14.89 ± 0.56 | 11.46 ± 0.69 | 8.25 ± 0.36 | 18.83 ± 0.91 |
L2 | >200 | >200 | >200 | >200 | >200 |
C2 | 28.91 ± 1.79 | 5.04 ± 0.42 | 5.88 ± 0.40 | 6.97 ± 0.52 | 21.86 ± 1.03 |
L3 | >200 | >200 | >200 | >200 | >200 |
C3 | 22.78 ± 1.14 | 12.00 ± 0.36 | 7.09 ± 0.53 | 10.55 ± 0.74 | 25.17 ± 0.85 |
L4 | >200 | >200 | >200 | >200 | >200 |
C4 | 37.80 ± 3.11 | 6.72. ± 0.12 | 5.92 ± 0.54 | 9.27 ± 0.11 | 18.25 ± 1.37 |
Etoposide * | 10.20 ± 0.83 | 43.21 ± 2.75 | >100 | >100 | 83.53 ± 3.19 |
Microorganism/Compounds | L2 | C2 | L3 | C3 | L4 | C4 |
---|---|---|---|---|---|---|
MIC (mg/L) * | ||||||
Yeasts | ||||||
C. albicans ATCC 102231 | 500 | 1000 | 250 | 1000 | 1000 | 500 |
C. parapsilosis ATCC 22019 | 1000 | 1000 | 125 | 1000 | >1000 | >1000 |
C. glabrata ATCC 90030 | >1000 | >1000 | 250 | 1000 | 1000 | >1000 |
Ligands/ Complexes | DDPH | ABTS |
---|---|---|
L1 | NR * | 183.21 ± 2.45 |
C1 | 37.45 ± 0.66 | 112.67 ± 1.8 |
L2 | NR * | 82.08 ± 2.77 |
C2 | 401.52 ± 2.48 | 107.14 ± 1.42 |
L3 | NR * | 96.67 ± 2.84 |
C3 | 380.65 ± 2.74 | 106.19 ± 2.55 |
L4 | NR * | 108.59 ± 1.51 |
C4 | 26.46 ± 1.04 | 72.5 ± 0.97 |
Ascorbic acid | 11.65 ± 0.54 | 20.15 ± 0.33 |
Physicochemical Properties | Lipophilicity | Water Solubility | Pharmacokinetics | Drug Likeness | |||||||
---|---|---|---|---|---|---|---|---|---|---|---|
mol. wt. (g/mol) | ROTB (n) | HBA (n) | HBD (n) | TPSA | CLogP o/w | Solubility Class | GI Absorption | BBB Permeant | Lipinski Filter | BS | |
Rule | <500 | <10 | <10 | <5 | - | <5 | - | - | - | - | - |
C1 | 530.89 | 2 | 4 | 0 | 66.40 | 3.04 | Soluble(p) | High | Yes | Yes(1) | 0.55 |
C2 | 560.92 | 2 | 4 | 2 | 90.46 | 2.48 | Soluble(p) | High | No | Yes(1) | 0.55 |
C3 | 361.71 | 1 | 2 | 0 | 36.44 | 1.87 | Soluble(m) | High | Yes | Yes(0) | 0.55 |
C4 | 375.74 | 2 | 2 | 0 | 36.44 | 2.14 | Soluble(m) | High | Yes | Yes(0) | 0.55 |
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Balewski, Ł.; Plech, T.; Korona-Głowniak, I.; Hering, A.; Szczesio, M.; Olczak, A.; Bednarski, P.J.; Kokoszka, J.; Kornicka, A. Copper(II) Complexes with 1-(Isoquinolin-3-yl)heteroalkyl-2-ones: Synthesis, Structure and Evaluation of Anticancer, Antimicrobial and Antioxidant Potential. Int. J. Mol. Sci. 2024, 25, 8. https://doi.org/10.3390/ijms25010008
Balewski Ł, Plech T, Korona-Głowniak I, Hering A, Szczesio M, Olczak A, Bednarski PJ, Kokoszka J, Kornicka A. Copper(II) Complexes with 1-(Isoquinolin-3-yl)heteroalkyl-2-ones: Synthesis, Structure and Evaluation of Anticancer, Antimicrobial and Antioxidant Potential. International Journal of Molecular Sciences. 2024; 25(1):8. https://doi.org/10.3390/ijms25010008
Chicago/Turabian StyleBalewski, Łukasz, Tomasz Plech, Izabela Korona-Głowniak, Anna Hering, Małgorzata Szczesio, Andrzej Olczak, Patrick J. Bednarski, Jakub Kokoszka, and Anita Kornicka. 2024. "Copper(II) Complexes with 1-(Isoquinolin-3-yl)heteroalkyl-2-ones: Synthesis, Structure and Evaluation of Anticancer, Antimicrobial and Antioxidant Potential" International Journal of Molecular Sciences 25, no. 1: 8. https://doi.org/10.3390/ijms25010008