Discovery of A Novel Series of Quinazoline–Thiazole Hybrids as Potential Antiproliferative and Anti-Angiogenic Agents
Abstract
:1. Introduction
2. Structural Design and Rationale
3. Materials and Methods
3.1. Materials and Measurements
3.2. Chemistry
3.2.1. Synthesis of Intermediate (1)
3.2.2. Synthesis of Intermediate (2)
3.2.3. Synthesis of Compounds SA01–SA07
3.3. In Vitro Cytotoxicity Evaluation
3.4. Molecular Docking Studies
3.5. Molecular Dynamics Studies
3.6. MM-PBSA Free Energy Calculation
3.7. Density Function Theory (DFT) Calculations
3.8. Wound Healing (Scratch) Assay
3.9. Chorioallantoic Egg Membrane (CAM) Assay
3.10. In Silico Physicochemical and Pharmacokinetics Predictions
4. Results and Discussion
4.1. Chemistry
4.2. In Vitro Cytotoxicity Evaluation
4.3. Molecular Docking Studies
4.4. Molecular Dynamics Studies
4.5. MM-PBSA Free Energy Calculation
4.6. FMO Analysis and Chemical Reactivity Descriptors
4.7. Wound Healing (Scratch) Assay
4.8. Chorioallantoic Egg Membrane (CAM) Assay
4.9. In Silico Physicochemical and Pharmacokinetics Prediction
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Comp. | Evaluated Cell Lines | Selectivity Index | |||
---|---|---|---|---|---|
EA.hy926 | HepG2 | BJ | 1 SIa | 2 SIb | |
SA01 | 3.64 | 31.20 | 36.25 | 9.96 | 1.16 |
SA02 | 0.93 | 2.34 | 2.35 | 2.53 | 1.00 |
SA03 | 0.79 | 4.24 | 2.84 | 3.59 | 0.67 |
SA04 | 0.98 | 2.72 | 6.79 | 6.93 | 2.50 |
SA05 | 1.40 | 1.83 | 2.67 | 1.91 | 1.46 |
SA06 | >10 | >100 | >100 | - | - |
SA07 | 5.85 | 27.30 | 23.76 | 4.06 | 0.87 |
Sorafenib | 6.62 | 6.28 | 13.24 | 2.00 | 2.11 |
System Evaluated | RMSD—Protein (nm) 1 | RMSF Amino Acid αCarbons (nm) 2 | RMSF Amino Acid Sidechains (nm) 3 | RMSD—Ligand (nm) 4 | Rg Protein(nm) 5 | NoHB Protein–Ligand (no/ns) 6 |
---|---|---|---|---|---|---|
apo VEGFR2 receptor + SA01 | 0.22 | 0.11 | 0.17 | 0.17 | 2.07 | 0.98 |
apo VEGFR2 receptor + SA02 | 0.21 | 0.12 | 0.17 | 0.10 | 2.06 | 0.91 |
apo VEGFR2 receptor + SA03 | 0.16 | 0.10 | 0.15 | 0.13 | 2.04 | 0.94 |
apo VEGFR2 receptor + SA04 | 0.23 | 0.11 | 0.16 | 0.10 | 2.06 | 0.98 |
apo VEGFR2 receptor + SA05 | 0.19 | 0.10 | 0.16 | 0.10 | 2.05 | 0.99 |
apo VEGFR2 receptor + SA06 | 0.31 | 0.09 | 0.14 | 0.19 | 2.07 | 0.98 |
apo VEGFR2 receptor + SA07 | 0.23 | 0.16 | 0.21 | 0.15 | 2.03 | 1.60 |
apo VEGFR2 receptor + SFN | 0.18 | 0.13 | 0.17 | 0.12 | 2.05 | 1.00 |
Number of H-Bond Interactions (% of Total Interactions) | |||||||||
---|---|---|---|---|---|---|---|---|---|
Lys868 | Glu885 | Cys919 | Cys1024 | Ile1025 | His1026 | Arg1027 | Asp1046 | Total H-Bonds | |
SA01 | 18 (0.18%) | 6959 (69.59%) | 1762 (17.62%) | - | 194 (1.94%) | - | - | 882 (8.82%) | 9815 |
SA02 | 18 (0.20%) | 6605 (66.05%) | 1525 (15.25%) | - | - | - | 2 (0.02%) | 946 (9.46%) | 9096 |
SA03 | 20 (0.21%) | 7066 (70.66%) | 1300 (13.00%) | - | 1 (0.01%) | - | 137 (1.37%) | 839 (8.39%) | 9363 |
SA04 | 3 (0.03%) | 7556 (75.56%) | 1275 (12.75%) | 3 (0.03%) | 20 (0.20%) | - | 10 (0.10%) | 876 (8.76%) | 9743 |
SA05 | 5 (0.05%) | 7329 (73.29%) | 1389 (13.75%) | - | 88 (0.88%) | - | 11 (0.11%) | 1082 (10.82%) | 9904 |
SA06 | 56 (0.57%) | 7493 (74.93%) | 1590 (15.75%) | - | - | - | - | 669 (6.69%) | 9808 |
SA07 | 4 (0.02%) | 7355 (73.55%) | 1886 (18.86%) | - | 5288 (52.88%) | - | 495 (4.95%) | 1011 (10.11%) | 16039 |
Sorafenib | - | 3825 (38.25%) | 178 (1.78%) | 13 (0.13%) | - | 13 (0.13%) | - | 5833 (58.33%) | 9866 |
Compound | ΔG (±SD *) | van der Waals (±SD *) | Electrostatic (±SD *) | Solvation (±SD *) |
---|---|---|---|---|
SA02 | −65.38 ± 4.13 | −58.48 ± 3.26 | −32.95 ± 3.93 | 26.06 ± 3.24 |
SA03 | −47.20 ± 11.74 | −46.68 ± 10.66 | −24.37 ± 3.94 | 23.84 ± 3.65 |
SA04 | −64.21 ± 4.18 | −58.87 ± 3.29 | −27.99 ± 4.33 | 22.66 ± 3.45 |
SA05 | −71.23 ± 5.29 | −64.37 ± 3.33 | −33.84 ± 4.39 | 26.97 ± 3.58 |
sorafenib | −69.39 ± 3.63 | −59.19 ± 2.81 | −39.67 ± 3.76 | 29.47 ± 2.65 |
FMO Analysis | SA01 | SA02 | SA03 | SA04 | SA05 | SA06 | SA07 | Sorafenib |
---|---|---|---|---|---|---|---|---|
HOMO (eV) | −5.08 | −5.3 | −5.37 | −5.47 | −5.57 | −5.26 | −5.22 | −6.04 |
LUMO (eV) | −1.5 | −1.55 | −1.95 | −1.63 | −1.73 | −1.49 | −1.54 | −1.45 |
Energy gap (eV) | 3.58 | 3.75 | 3.42 | 3.84 | 3.84 | 3.77 | 3.68 | 4.59 |
Chemical reactivity descriptors | ||||||||
Ionization potential (I) (eV) | 5.08 | 5.3 | 5.37 | 5.47 | 5.57 | 5.26 | 5.22 | 6.04 |
Electronic affinity (A) (eV) | 1.5 | 1.55 | 1.95 | 1.63 | 1.73 | 1.49 | 1.54 | 1.45 |
Chemical potential (μ) (eV) | −3.29 | −3.42 | −3.66 | −3.55 | −3.65 | −3.37 | −3.38 | −3.74 |
Chemical hardness (η) (eV) | 1.79 | 1.87 | 1.71 | 1.92 | 1.92 | 1.88 | 1.84 | 2.29 |
Global softness (S) (eV) | 0.89 | 0.93 | 0.85 | 0.96 | 0.96 | 0.94 | 0.92 | 1.14 |
Electrophilicity index (ω)(eV) | 9.68 | 10.99 | 11.45 | 12.09 | 12.79 | 10.73 | 10.51 | 16.09 |
Nucleophilicity index (N) (eV−1) | 0.10 | 0.09 | 0.08 | 0.08 | 0.07 | 0.09 | 0.09 | 0.06 |
Additional electronic charges (∆N) | 1.83 | 1.82 | 2.14 | 1.84 | 1.90 | 1.79 | 1.83 | 1.63 |
Dipole moment (Debye) | 2.96 | 2.71 | 3.06 | 3.74 | 5.59 | 2.84 | 5.35 | 6.68 |
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Șandor, A.; Fizeșan, I.; Ionuț, I.; Marc, G.; Moldovan, C.; Oniga, I.; Pîrnău, A.; Vlase, L.; Petru, A.-E.; Macasoi, I.; et al. Discovery of A Novel Series of Quinazoline–Thiazole Hybrids as Potential Antiproliferative and Anti-Angiogenic Agents. Biomolecules 2024, 14, 218. https://doi.org/10.3390/biom14020218
Șandor A, Fizeșan I, Ionuț I, Marc G, Moldovan C, Oniga I, Pîrnău A, Vlase L, Petru A-E, Macasoi I, et al. Discovery of A Novel Series of Quinazoline–Thiazole Hybrids as Potential Antiproliferative and Anti-Angiogenic Agents. Biomolecules. 2024; 14(2):218. https://doi.org/10.3390/biom14020218
Chicago/Turabian StyleȘandor, Alexandru, Ionel Fizeșan, Ioana Ionuț, Gabriel Marc, Cristina Moldovan, Ilioara Oniga, Adrian Pîrnău, Laurian Vlase, Andreea-Elena Petru, Ioana Macasoi, and et al. 2024. "Discovery of A Novel Series of Quinazoline–Thiazole Hybrids as Potential Antiproliferative and Anti-Angiogenic Agents" Biomolecules 14, no. 2: 218. https://doi.org/10.3390/biom14020218
APA StyleȘandor, A., Fizeșan, I., Ionuț, I., Marc, G., Moldovan, C., Oniga, I., Pîrnău, A., Vlase, L., Petru, A.-E., Macasoi, I., & Oniga, O. (2024). Discovery of A Novel Series of Quinazoline–Thiazole Hybrids as Potential Antiproliferative and Anti-Angiogenic Agents. Biomolecules, 14(2), 218. https://doi.org/10.3390/biom14020218