Novel 1,2,3-Triazole-Containing Quinoline–Benzimidazole Hybrids: Synthesis, Antiproliferative Activity, In Silico ADME Predictions, and Docking
Abstract
:1. Introduction
2. Results and Discussion
2.1. Chemistry
2.2. Biological Activity
2.2.1. Evaluation of Antiproliferative Activity of the Novel Compounds
2.2.2. Cell Cycle Perturbation
2.3. Absorption, Distribution, Metabolism, Excretion (ADME), and Toxicity Properties
2.4. Molecular Docking Study
3. Materials and Methods
3.1. Chemistry
3.1.1. General Procedure for the Synthesis of Compounds 6, 7, 12 and 13
4-((1-(7-chloroquinolin-4-yl)-1H-1,2,3-triazol-4-yl)methoxy)benzaldehyde (6)
3-bromo-4-{[1-(7-chloroquinolin-4-yl)-1H-1,2,3-triazol-4-yl]methoxy}benzaldehyde (7)
4-[(1-{2-[(7-chloroquinolin-4-yl)amino]ethyl}-1H-1,2,3-triazol-4-yl)methoxy]benzaldehyde (12)
3-bromo-4-[(1-{2-[(7-chloroquinolin-4-yl)amino]ethyl}-1H-1,2,3-triazol-4-yl)methoxy]benzaldehyde (13)
3.1.2. General Procedure for the Synthesis of Compounds 9a–10e and 14a–15e
4-(4-{[4-(1H-benzo[d]imidazol-2-yl)phenoxy]methyl}-1H-1,2,3-triazol-1-yl)-7-chloroquinoline (9a)
7-chloro-4-(4-{[4-(5-chloro-1H-benzo[d]imidazol-2-yl)phenoxy]methyl}-1H-1,2,3-triazol-1-yl)quinoline (9b)
7-chloro-4-(4-{[4-(5-methoxy-1H--benzo[d]imidazol-2-yl)phenoxy]methyl}-1H-1,2,3-triazol-1-yl)quinoline (9c)
2-(4-{[1-(7-chloroquinolin-4-yl)-1H-1,2,3-triazol-4-yl]methoxy}phenyl)-1H-benzo[d]imidazol-5-carboximidamide trihydrochloride (9d)
2-(4-{[1-(7-chloroquinolin-4-yl)-1H-1,2,3-triazol-4-yl]methoxy}phenyl)-N-propyl-1H-benzo[d]imidazol-5-carboximidamide trihydrochloride (9e)
4-(4-{[4-(1H-benzo[d]imidazol-2-yl)-2-bromophenoxy]methyl}-1H-1,2,3-triazol-1-yl)-7-chloroquinoline (10a)
4-(4-{[2-bromo-4-(5-chloro-1H-benzo[d]imidazol-2-yl)phenoxy]methyl}-1H-1,2,3-triazol-1-yl)-7-chloroquinoline (10b)
4-(4-{[2-bromo-4-(5-methoxy-1H-benzo[d]imidazol-2-yl)phenoxy]methyl}-1H-1,2,3-triazol-1-yl)-7-chloroquinoline (10c)
2-(3-bromo-4-{[1-(7-chloroquinolin-4-yl)-1H-1,2,3-triazol-4-yl]methoxy}phenyl)-1H-benzo[d]imidazol-5-carboximidamide trihydrochloride (10d)
2-(3-bromo-4-{[1-(7-chloroquinolin-4-yl)-1H-1,2,3-triazol-4-yl]methoxy}phenyl)-N-propyl-1H-benzo[d]imidazol-5-carboximidamide trihydrochloride (10e)
N-[2-(4-{[4-(1H-benzo[d]midazole-2-yl)phenoxy]methyl}-1H-1,2,3-triazol-1-yl)ethyl]-7-chloroquinolin-4-amine (14a)
7-chloro-N-[2-(4-{[4-(5-chloro-1H-benzo[d]imidazol-2-yl)phenoxy]methyl}-1H-1,2,3-triazol-1-yl)ethyl]quinolin-4-amine (14b)
7-chloro-N-[2-(4-{[4-(5-methoxy-1H-benzo[d]imidazol-2-yl)phenoxy]methyl}-1H-1,2,3-triazol-1-yl)ethyl]quinolin-4-amine (14c)
2-{4-[(1-{2-[(7-chloroquinolin-4-yl)amino]ethyl}-1H-1,2,3-triazol-4-yl)methoxy]phenyl}-1H-benzo[d]imidazol-5-carboximidamide trihydrochloride (14d)
2-{4-[(1-{2-[(7-chloroquinolin-4-yl)amino]ethyl}-1H-1,2,3-triazol-4-yl)methoxy]phenyl}-N-propyl-1H-benzo[d]imidazol-5-carboximidamide trihydrochloride (14e)
N-[2-(4-{[4-(1H-benzo[d]imidazol-2-yl)-2-bromophenoxy]methyl}-1H-1,2,3-triazol-1-yl)ethyl]-7-chloroquinolin-4-amine (15a)
N-[2-(4-{[2-bromo-4-(5-chloro-1H-benzo[d]imidazol-2-yl)phenoxy]methyl}-1H-1,2,3-triazol-1-yl)ethyl]-7-chloroquinolin-4-amine (15b)
N-[2-(4-{[2-bromo-4-(5-methoxy-1H-benzo[d]imidazol-2-yl)phenoxy]methyl}-1H-1,2,3-triazol-1-yl)ethyl]-7-chloroquinolin-4-amine (15c)
2-{3-bromo-4-[(1-{2-[(7-chloroquinolin-4-yl)amino]ethyl}-1H-1,2,3-triazol-4-yl)methoxy]phenyl}-1H-benzo[d]imidazol-5-carboximidamide trihydrochloride (15d)
2-{3-bromo-4-[(1-{2-[(7-chloroquinolin-4-yl)amino]ethyl}-1H-1,2,3-triazol-4-yl)methoxy]phenyl}-N-propyl-1H-benzo[d]imidazol-5-carboximidamide trihydrochloride (15e)
3.2. Biological Activity
3.2.1. Cell Lines and Cell Culturing
3.2.2. Proliferation Assay
3.2.3. Cell Cycle Analysis
3.3. Computational Methods
3.3.1. Calculation of ADME Properties
3.3.2. Molecular Docking
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Sample Availability
References
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Comp. | R1 | R2 | MRC-5 | HeLa | CaCo-2 | THP-1 | Hut78 | HL-60 |
---|---|---|---|---|---|---|---|---|
9a | H | H | >100 | >100 | >100 | >100 | 100 | >100 |
9b | H | Cl | 100 | 94.1 | >100 | >100 | 92.9 ± 4.3 | >100 |
9c | H | OCH3 | 2.71 | 7.53 | 8.3 | 0.18 | 0.2 | 1.02 |
9d | H | >100 | >100 | >100 | >100 | 2.52 | >100 | |
9e | H | >100 | >100 | >100 | >100 | 10.2 | 98.3 | |
10a | Br | H | 52.1 | 10.0 | 63.8 | 9.6 | 5.88 | 76.1 |
10b | Br | Cl | >100 | 8.11 | 10.9 | 10.6 | 6.43 | 55.2 |
10c | Br | OCH3 | 8.54 | 9.86 | 9.92 | 6.23 | 3.89 | 18.2 |
10d | Br | >100 | >100 | >100 | >100 | >100 | >100 | |
10e | Br | >100 | >100 | >100 | >100 | 9.68 | 93.2 | |
14a | H | H | >100 | >100 | >100 | >100 | >100 | >100 |
14b | H | Cl | >100 | >100 | >100 | >100 | >100 | >100 |
14c | H | OCH3 | >100 | >100 | >100 | 7.31 | >100 | >100 |
14d | H | >100 | >100 | >100 | >100 | 10.51 | >100 | |
14e | H | >100 | >100 | >100 | >100 | 10.86 | >100 | |
15a | Br | H | >100 | >100 | >100 | 4.66 | 7.88 | 11.63 |
15b | Br | Cl | >100 | >100 | >100 | 2.06 | 4.91 | 1.24 |
15c | Br | OCH3 | >100 | >100 | >100 | 1.65 | 3.98 | 2.62 |
15d | Br | >100 | >100 | >100 | >100 | >100 | >100 | |
15e | Br | >100 | >100 | >100 | >100 | 7.83 | >100 | |
5-FU | 54.1 | 8.2 | 5.9 | 76.4 | >100 | >100 |
Comp. | MW * | Csp3 | RB | HBA | HBD | TPSA | XLOGP3 | MLOGP | ESOL Log S | Water Sol. | GIA | BBBP | PgpS | LR |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
9a | 452.9 | 0.04 | 5 | 5 | 1 | 81.51 | 4.97 | 3.49 | −6.12 | Poorly | High | No | Yes | 0 |
9b | 487.34 | 0.04 | 5 | 5 | 1 | 81.51 | 5.6 | 3.96 | −6.71 | Poorly | High | No | Yes | 0 |
9c | 482.92 | 0.08 | 6 | 6 | 1 | 90.74 | 4.94 | 3.17 | −6.18 | Poorly | High | No | Yes | 0 |
9d | 495.94 | 0.04 | 6 | 5 | 3 | 133.12 | 3.94 | 2.87 | −5.62 | Poorly | High | No | Yes | 0 |
9e | 538.02 | 0.14 | 9 | 5 | 3 | 119.13 | 5.23 | 3.45 | −6.45 | Poorly | High | No | Yes | 1 |
10a | 531.79 | 0.04 | 5 | 5 | 1 | 81.51 | 5.66 | 4.32 | −7.03 | Poorly | High | No | No | 2 |
10b | 566.24 | 0.04 | 5 | 5 | 1 | 81.51 | 6.29 | 4.79 | −7.62 | Poorly | Low | No | No | 2 |
10c | 561.82 | 0.08 | 6 | 6 | 1 | 90.74 | 5.63 | 3.73 | −7.09 | Poorly | Low | No | No | 1 |
10d | 574.84 | 0.04 | 6 | 5 | 3 | 133.12 | 4.63 | 3.43 | −6.52 | Poorly | Low | No | Yes | 1 |
10e | 616.92 | 0.14 | 9 | 5 | 3 | 119.13 | 5.92 | 4.01 | −7.36 | Poorly | Low | No | No | 1 |
14a | 495.96 | 0.11 | 8 | 5 | 2 | 93.54 | 4.93 | 3.1 | −6.11 | Poorly | High | No | Yes | 0 |
14b | 530.41 | 0.11 | 8 | 5 | 2 | 93.54 | 5.55 | 3.56 | −6.7 | Poorly | High | No | No | 1 |
14c | 525.99 | 0.14 | 9 | 6 | 2 | 102.77 | 4.9 | 2.78 | −6.18 | Poorly | High | No | Yes | 1 |
14d | 539.01 | 0.11 | 9 | 5 | 4 | 145.15 | 3.89 | 2.49 | −5.61 | Poorly | Low | No | Yes | 1 |
14e | 581.09 | 0.19 | 12 | 5 | 4 | 131.16 | 5.19 | 3.06 | −6.45 | Poorly | Low | No | No | 1 |
15a | 564.86 | 0.15 | 9 | 5 | 2 | 93.01 | 3.74 | 3.03 | −5.52 | Moderately | High | No | Yes | 1 |
15b | 599.31 | 0.15 | 9 | 5 | 2 | 93.01 | 4.37 | 3.49 | −6.11 | Poorly | High | No | No | 1 |
15c | 594.89 | 0.19 | 10 | 6 | 2 | 102.24 | 3.72 | 2.71 | −5.6 | Moderately | High | No | Yes | 1 |
15d | 607.91 | 0.15 | 10 | 5 | 4 | 144.62 | 2.71 | 2.69 | −5.04 | Moderately | Low | No | Yes | 1 |
15e | 649.99 | 0.23 | 13 | 5 | 4 | 130.63 | 2.71 | 2.69 | −5.04 | Moderately | Low | No | Yes | 1 |
Compound | Energy | VDW | HBond | Elec |
---|---|---|---|---|
14e | −140.44 | 79.20 | 20.80 | 0.00 |
STU | −137.99 | 89.85 | 10.15 | 0.00 |
9e | −131.00 | 79.16 | 20.84 | 0.00 |
14d | −127.85 | 80.96 | 19.04 | 0.00 |
9d | −127.67 | 72.83 | 24.98 | 2.19 |
10e | −124.68 | 86.23 | 13.77 | 0.00 |
9c | −123.88 | 84.30 | 15.70 | 0.00 |
10c | −123.41 | 78.59 | 21.41 | 0.00 |
9a | −122.31 | 79.50 | 20.50 | 0.00 |
14a | −120.23 | 83.55 | 16.45 | 0.00 |
10d | −119.16 | 81.20 | 16.97 | 1.83 |
10b | −118.41 | 74.77 | 25.23 | 0.00 |
14c | −116.35 | 83.43 | 16.57 | 0.00 |
9b | −115.47 | 85.73 | 14.27 | 0.00 |
15e | −114.44 | 84.73 | 15.27 | 0.00 |
15c | −111.56 | 87.59 | 12.41 | 0.00 |
14b | −110.44 | 81.86 | 18.14 | 0.00 |
10a | −106.61 | 83.64 | 16.36 | 0.00 |
15a | −105.91 | 88.73 | 11.27 | 0.00 |
15d | −105.48 | 88.01 | 11.99 | 0.00 |
15b | −101.95 | 72.16 | 27.84 | 0.00 |
H Bond | Energy | Van der Waals Interaction | Energy |
---|---|---|---|
M-Ile34 | −2.30 | M-Ile34 | −3.95 |
M-His36 | −3.50 | M-Gly35 | −7.69 |
S-Glu76 | −6.90 | M-His36 | −7.87 |
M-Leu80 | −1.60 | S-His36 | −1.21 |
M-Ile89 | −3.50 | S-Phe39 | −3.82 |
S-Asp114 | −3.50 | S-Val42 | −3.97 |
S-Glu117 | −5.41 | S-Lys57 | −6.50 |
M-Asp169 | −2.50 | M-Leu80 | −3.34 |
S-Leu80 | −11.43 | ||
M-Ile89 | −1.89 | ||
M-Gln90 | −7.64 | ||
S-Met105 | −8.39 | ||
S-Asp114 | −2.81 | ||
S-Glu117 | −3.38 | ||
M-Gly168 | −4.74 | ||
M-Asp169 | −3.88 | ||
S-Asp169 | −6.43 | ||
S-Phe170 | −3.39 | ||
S-Met312 | −2.46 | ||
S-Lys314 | −5.48 |
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Krstulović, L.; Mišković Špoljarić, K.; Rastija, V.; Filipović, N.; Bajić, M.; Glavaš-Obrovac, L. Novel 1,2,3-Triazole-Containing Quinoline–Benzimidazole Hybrids: Synthesis, Antiproliferative Activity, In Silico ADME Predictions, and Docking. Molecules 2023, 28, 6950. https://doi.org/10.3390/molecules28196950
Krstulović L, Mišković Špoljarić K, Rastija V, Filipović N, Bajić M, Glavaš-Obrovac L. Novel 1,2,3-Triazole-Containing Quinoline–Benzimidazole Hybrids: Synthesis, Antiproliferative Activity, In Silico ADME Predictions, and Docking. Molecules. 2023; 28(19):6950. https://doi.org/10.3390/molecules28196950
Chicago/Turabian StyleKrstulović, Luka, Katarina Mišković Špoljarić, Vesna Rastija, Nikolina Filipović, Miroslav Bajić, and Ljubica Glavaš-Obrovac. 2023. "Novel 1,2,3-Triazole-Containing Quinoline–Benzimidazole Hybrids: Synthesis, Antiproliferative Activity, In Silico ADME Predictions, and Docking" Molecules 28, no. 19: 6950. https://doi.org/10.3390/molecules28196950