1,2,4-Triazole-Tethered Indolinones as New Cancer-Fighting Small Molecules Targeting VEGFR-2: Synthesis, Biological Evaluations and Molecular Docking
Abstract
:1. Introduction
2. Results and Discussion
2.1. Chemistry
2.2. Biological Evaluation
2.2.1. In Vitro Anti-Proliferative Activity against PANC1 and HepG2 Cell Lines
2.2.2. VEGFR-2 Inhibitory Activities
2.3. In Silico ADME Study
2.4. Molecular Modelling
2.4.1. Molecular Docking
2.4.2. Molecular Dynamics
3. Materials and Methods
3.1. Chemistry
3.1.1. Synthesis of 4-Nitrohippuric Acid (3)
3.1.2. Synthesis of 4-Aminohippuric Acid (4)
3.1.3. Synthesis of N-{4-[(4-[2-Arylhydrazin-1-ylidene]-5-oxo-4,5-dihydro-1,3-oxazol-2-yl]phenyl}acetamides (8a–b)
N-{4-[(4-[2-(4-Fluorophenyl)hydrazin-1-ylidene]-5-oxo-4,5-dihydro-1,3-oxazol-2-yl]phenyl}acetamide (8a)
N-{4-[(4-[2-(4-Chlorophenyl)hydrazin-1-ylidene]-5-oxo-4,5-dihydro-1,3-oxazol-2-yl]phenyl}acetamide (8b)
3.1.4. Synthesis of N-{4-[1-Aryl-3-(hydrazinecarbonyl)-1H-1,2,4-triazol-5-yl]phenyl}acetamide (9a–b)
N-{4-[1-(4-Fluorophenyl)-3-(hydrazinecarbonyl)-1H-1,2,4-triazol-5-yl]phenyl}acetamide (9a)
N-{4-[1-(4-Chlorophenyl)-3-(hydrazinecarbonyl)-1H-1,2,4-triazol-5-yl]phenyl}acetamide (9b)
3.1.5. Synthesis of N-[4-(1-Aryl-3-{N′-[2-oxo-2,3-dihydro-1H-indol-3-ylidene]hydrazinecarbonyl}-1H-1,2,4-triazol-5-yl)phenyl]acetamides (11a–l and 14a–d)
N-{4-[1-(4-Fluorophenyl)-3-{N′-[2-oxo-2,3-dihydro-1H-indol-3-ylidene]hydrazinecarbonyl}-1H-1,2,4-triazol-5-yl]phenyl}acetamide (11a)
N-[4-(3-{N′-[5-Fluoro-2-oxo-2,3-dihydro-1H-indol-3-ylidene]hydrazinecarbonyl}-1-(4-fluorophenyl)-1H-1,2,4-triazol-5-yl)phenyl]acetamide (11b)
N-[4-(3-{N′-[5-Chloro-2-oxo-2,3-dihydro-1H-indol-3-ylidene]hydrazinecarbonyl}-1-(4-fluorophenyl)-1H-1,2,4-triazol-5-yl)phenyl]acetamide (11c)
N-[4-(3-{N′-[5-Bromo-2-oxo-2,3-dihydro-1H-indol-3-ylidene]hydrazinecarbonyl}-1-(4-fluorophenyl)-1H-1,2,4-triazol-5-yl)phenyl]acetamide (11d)
N-{4-[1-(4-Fluorophenyl)-3-{N′-[5-methoxy-2-oxo-2,3-dihydro-1H-indol-3-ylidene]hydrazinecarbonyl}-1H-1,2,4-triazol-5-yl]phenyl}acetamide (11e)
N-{4-[1-(4-Fluorophenyl)-3-{N′-[5-nitro-2-oxo-2,3-dihydro-1H-indol-3-ylidene]hydrazinecarbonyl}-1H-1,2,4-triazol-5-yl]phenyl}acetamide (11f)
N-{4-[1-(4-Chlorophenyl)-3-{N′-[2-oxo-2,3-dihydro-1H-indol-3-ylidene]hydrazinecarbonyl}-1H-1,2,4-triazol-5-yl]phenyl}acetamide (11g)
N-{4-[1-(4-Chlorophenyl)-3-{N′-[5-fluoro-2-oxo-2,3-dihydro-1H-indol-3-ylidene]hydrazinecarbonyl}-1H-1,2,4-triazol-5-yl]phenyl}acetamide (11h)
N-[4-(3-{N′-[5-Chloro-2-oxo-2,3-dihydro-1H-indol-3-ylidene]hydrazinecarbonyl}-1-(4-chlorophenyl)-1H-1,2,4-triazol-5-yl)phenyl]acetamide (11i)
N-[4-(3-{N′-[5-Bromo-2-oxo-2,3-dihydro-1H-indol-3-ylidene]hydrazinecarbonyl}-1-(4-chlorophenyl)-1H-1,2,4-triazol-5-yl)phenyl]acetamide (11j)
N-{4-[1-(4-Chlorophenyl)-3-{N′-[5-methoxy-2-oxo-2,3-dihydro-1H-indol-3-ylidene]hydrazinecarbonyl}-1H-1,2,4-triazol-5-yl]phenyl}acetamide (11k)
N-{4-[1-(4-Chlorophenyl)-3-{N′-[5-nitro-2-oxo-2,3-dihydro-1H-indol-3-ylidene]hydrazinecarbonyl}-1H-1,2,4-triazol-5-yl]phenyl}acetamide (11l)
N-{4-[1-(4-Fluorophenyl)-3-{N′-[1-methyl-2-oxo-2,3-dihydro-1H-indol-3-ylidene]hydrazinecarbonyl}-1H-1,2,4-triazol-5-yl]phenyl}acetamide (14a)
N-[4-(3-{N′-[1-Benzyl-5-bromo-2-oxo-2,3-dihydro-1H-indol-3-ylidene]hydrazinecarbonyl}-1-(4-fluorophenyl)-1H-1,2,4-triazol-5-yl)phenyl]acetamide (14b)
N-{4-[1-(4-Chlorophenyl)-3-{N′-[1-methyl-2-oxo-2,3-dihydro-1H-indol-3-ylidene]hydrazinecarbonyl}-1H-1,2,4-triazol-5-yl]phenyl}acetamide (14c)
N-[4-(3-{N′-[1-Benzyl-5-bromo-2-oxo-2,3-dihydro-1H-indol-3-ylidene]hydrazinecarbonyl}-1-(4-chlorophenyl)-1H-1,2,4-triazol-5-yl)phenyl]acetamide (14d)
3.2. Biological Evaluation
3.3. Molecular Docking
3.4. Molecular Dynamics
3.5. In Silico ADME Study
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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11a–l | 14a–d | ||||
---|---|---|---|---|---|
Comp. | R | R1 | R2 | IC50 (µM) a | |
PANC1 | HepG2 | ||||
11a | F | H | --- | 4.29 ± 0.1 | 2.06 ± 0.03 |
11b | F | F | --- | 1.74 ± 0.02 | 1.17 ± 0.03 |
11c | F | Cl | --- | 0.98 ± 0.06 | 2.21 ± 0.03 |
11d | F | Br | --- | 1.16 ± 0.02 | 0.73 ± 0.02 |
11e | F | OCH3 | --- | 2.22 ± 0.07 | 0.76 ± 0.02 |
11f | F | NO2 | --- | 0.23 ± 0.01 | 2.41 ± 0.04 |
11g | Cl | H | --- | 0.77 ± 0.02 | 0.71 ± 0.01 |
11h | Cl | F | --- | 0.22 ± 0.01 | 1.27 ± 0.04 |
11i | Cl | Cl | --- | 3.75 ± 0.09 | 4.49 ± 0.15 |
11j | Cl | Br | --- | 1.68 ± 0.06 | 1.01 ± 0.02 |
11k | Cl | OCH3 | --- | 1.78 ± 0.04 | 0.73 ± 0.01 |
11l | Cl | NO2 | --- | 0.17 ± 0.01 | 1.73 ± 0.06 |
14a | F | H | CH3 | 4.05 ± 0.1 | 1.63 ± 0.02 |
14b | F | Br | C6H5 | 0.76 ± 0.04 | 0.98 ± 0 |
14c | Cl | H | CH3 | 0.2 ± 0 | 0.58 ± 0.01 |
14d | Cl | Br | C6H5 | 0.42 ± 0.01 | 0.92 ± 0.02 |
Dox. | 0.19 ± 0.01 | 0.43 ± 0.02 |
Comp. | IC50 (µM) |
---|---|
11d | 8.35 ± 0.62 |
11e | 11.74 ± 0.93 |
11g | 10.65 ± 0.71 |
11k | 13.22 ± 1.09 |
14c | 7.92 ± 0.48 |
Comp. | VEGFR-2 IC50 (nM) a |
---|---|
11d | 16.3 ± 0.42 |
11e | 48.4 ± 0.39 |
11g | 119.6 ± 1.8 |
11k | 41.3 ± 0.31 |
14c | 53.8 ± 0.61 |
Sorafenib | 29.7 ± 0.39 |
Compound | GI Absorption | BBB Permeant | Pgp Substrate | CYP1A2 Inhibitor | CYP2C19 Inhibitor | CYP2C9 Inhibitor | CYP2D6 Inhibitor | CYP3A4 Inhibitor | Lipinski #Violations | Veber #Violations |
---|---|---|---|---|---|---|---|---|---|---|
11a | High | No | No | No | Yes | Yes | No | Yes | 0 | 0 |
11b | High | No | No | No | Yes | Yes | No | Yes | 1 | 0 |
11c | High | No | No | No | Yes | Yes | No | Yes | 1 | 0 |
11d | High | No | No | No | Yes | Yes | No | Yes | 1 | 0 |
11e | Low | No | Yes | No | Yes | Yes | No | Yes | 2 | 0 |
11f | Low | No | No | No | No | Yes | No | Yes | 2 | 1 |
11g | High | No | No | No | Yes | Yes | No | Yes | 0 | 0 |
11h | High | No | No | No | Yes | Yes | No | Yes | 1 | 0 |
11i | High | No | No | No | Yes | Yes | No | Yes | 1 | 0 |
11j | Low | No | No | No | Yes | Yes | No | Yes | 1 | 0 |
11k | Low | No | No | No | Yes | Yes | No | Yes | 2 | 0 |
11l | Low | No | No | No | No | Yes | No | Yes | 2 | 1 |
14a | High | No | No | No | Yes | Yes | No | Yes | 0 | 0 |
14b | Low | No | No | No | Yes | Yes | No | No | 1 | 0 |
14c | High | No | No | No | Yes | Yes | No | Yes | 1 | 0 |
14d | Low | No | No | No | Yes | No | No | No | 2 | 0 |
Compound | Docking Score (kcal/mol) |
---|---|
11d | −9.6 |
11e | −8.3 |
11g | −7.1 |
11k | −8.5 |
14c | −8.0 |
Sorafenib | −9.5 |
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Elsawi, A.E.; Shahin, M.I.; Elbendary, H.A.; Al-Warhi, T.; Hassan, F.E.; Eldehna, W.M. 1,2,4-Triazole-Tethered Indolinones as New Cancer-Fighting Small Molecules Targeting VEGFR-2: Synthesis, Biological Evaluations and Molecular Docking. Pharmaceuticals 2024, 17, 81. https://doi.org/10.3390/ph17010081
Elsawi AE, Shahin MI, Elbendary HA, Al-Warhi T, Hassan FE, Eldehna WM. 1,2,4-Triazole-Tethered Indolinones as New Cancer-Fighting Small Molecules Targeting VEGFR-2: Synthesis, Biological Evaluations and Molecular Docking. Pharmaceuticals. 2024; 17(1):81. https://doi.org/10.3390/ph17010081
Chicago/Turabian StyleElsawi, Ahmed E., Mai I. Shahin, Hager A. Elbendary, Tarfah Al-Warhi, Fatma E. Hassan, and Wagdy M. Eldehna. 2024. "1,2,4-Triazole-Tethered Indolinones as New Cancer-Fighting Small Molecules Targeting VEGFR-2: Synthesis, Biological Evaluations and Molecular Docking" Pharmaceuticals 17, no. 1: 81. https://doi.org/10.3390/ph17010081
APA StyleElsawi, A. E., Shahin, M. I., Elbendary, H. A., Al-Warhi, T., Hassan, F. E., & Eldehna, W. M. (2024). 1,2,4-Triazole-Tethered Indolinones as New Cancer-Fighting Small Molecules Targeting VEGFR-2: Synthesis, Biological Evaluations and Molecular Docking. Pharmaceuticals, 17(1), 81. https://doi.org/10.3390/ph17010081