An Efficient Synthesis of 1-(1,3-Dioxoisoindolin-2-yl)-3-aryl Urea Analogs as Anticancer and Antioxidant Agents: An Insight into Experimental and In Silico Studies
Abstract
:1. Introduction
2. Results
2.1. Chemistry
2.2. Anticancer Activity
2.3. In Vitro EGFR Kinase Inhibition Assay
2.4. Molecular Docking Studies
2.5. Antioxidant Activity
2.6. ADMET Prediction
3. Discussion
4. Materials and Methods
4.1. General Procedure for the Synthesis of Phenyl(substituted phenyl)carbamate Analogs (3a–f)
4.2. Procedure for the Synthesis of Phthalimide (5)
4.3. Procedure for the Synthesis of 2-Aminoisoindoline-1,3-dione (6)
4.4. General Procedure for the Synthesis of 1-(1,3-Dioxoisoindolin-2-yl)-3-aryl Urea Analogs (7a–f)
4.5. Anticancer Activity
4.6. In Vitro EGFR Kinase Inhibition Assay
4.7. Molecular Docking Studies
4.8. Antioxidant Activity
4.9. ADMET Prediction
5. 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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S. No. | Compound | R | NSC Code | Rf * | % Yield | Mp (°C) | ||
---|---|---|---|---|---|---|---|---|
Found | Reported | Found | Reported | |||||
1 | 7a | 4-Fluoro | 838925 | 0.69 | 89 | 67.7 a | 248–250 | >245 a |
2 | 7b | 4-Chloro | 838926 | 0.71 | 90 | 86.2 a | 252–254 | >250 a |
3 | 7c | 4-Bromo | 838927 | 0.72 | 92 | 73.1 a | 250–252 | 250 a |
4 | 7d | 4-Methoxy | - | 0.67 | 83 | 35.9 a | >260 | >260 a |
5 | 7e | 2-Chloro | 838928 | 0.68 | 81 | 46 b | 140–142 | 139 b |
6 | 7f | 2-Methoxy | 838934 | 0.73 | 85 | - | 156–158 | - |
Panel | Cell Line | 7a | 7b | 7c | 7e | 7f |
---|---|---|---|---|---|---|
Leukemia | CCRF-CEM | 103.9 | 104.8 | 101.2 | 103.37 | 95.13 |
HL-60(TB) | 86.23 | 83.07 | 92.99 | 101.97 | 101.22 | |
K-562 | 100.3 | 91.98 | 92.8 | 110.7 | 92.54 | |
MOLT-4 | 98.29 | 101.1 | 99.67 | 97.49 | 106.2 | |
RPMI-8226 | 105.9 | 106.5 | 108.3 | 109.46 | 103.93 | |
SR | 94.86 | 96.2 | 94.2 | 92.66 | 93.35 | |
Non-small cell lung cancer | A549/ATCC | 99.08 | 102.7 | 101.2 | 103.02 | 103.59 |
EKVX | 89.44 | 80.73 | 75.46 | 90.83 | 91.2 | |
HOP-62 | 107.5 | 107.1 | 108.4 | 99.95 | 115.38 | |
HOP-92 | 120.9 | 109.3 | 107.7 | 110.12 | 115.4 | |
NCI-H226 | 99.82 | 94.57 | 91.94 | 96.96 | 100.71 | |
NCI-H23 | 102.4 | 93.59 | 93.98 | 100.32 | 97.03 | |
NCI-H322M | 94 | 96.1 | 98.49 | 101.21 | 95.89 | |
NCI-H460 | 116.7 | 121.1 | 107.8 | 106.44 | 118.73 | |
NCI-H522 | 96.78 | 94.82 | 96.41 | 97.3 | 96.7 | |
Colon cancer | COLO 205 | 111.6 | 111.5 | 108.9 | 100.1 | 113.79 |
HCC-2998 | 105.2 | 107.6 | 104.5 | 101.52 | 104.81 | |
HCT-116 | 97.82 | 100.6 | 97.06 | 104.92 | 110.15 | |
HCT-15 | 99.39 | 94.99 | 94.12 | 101.91 | 100.49 | |
HT29 | 103.4 | 109.3 | 107.1 | 104.06 | 113.18 | |
KM12 | 100.2 | 99.16 | 98.57 | 99.5 | 100.71 | |
SW-620 | 103.7 | 108.3 | 99.5 | 96.91 | 101.88 | |
CNS cancer | SF-268 | 97.06 | 97.16 | 96.17 | 94.28 | 104.11 |
SF-295 | 94.85 | 98.09 | 99.52 | 96.86 | 101.54 | |
SF-539 | 95.37 | 92.59 | 92.35 | 94.08 | 95.62 | |
SNB-19 | 97.85 | 96.23 | 96.31 | 98.24 | 97.73 | |
U251 | 103.1 | 107.2 | 105.5 | 104.47 | 104.72 | |
Melanoma | LOX IMVI | 96.84 | 87.19 | 84.52 | 92.19 | 96.42 |
MALME-3M | 93.65 | 94.22 | 96.35 | 94.53 | 94.69 | |
M14 | 101.2 | 101.9 | 101.8 | 101.76 | 104.17 | |
MDA-MB-435 | 97.22 | 96.66 | 96.81 | 100.53 | 99.08 | |
SK-MEL-28 | 99.56 | 102.6 | 104.4 | 104.47 | 101.02 | |
SK-MEL-5 | 92.01 | 86.59 | 90.69 | 92.19 | 93.38 | |
UACC-257 | 102 | 105.8 | 104.4 | 94.53 | 103.72 | |
UACC-62 | 90.53 | 85.6 | 80.81 | 101.76 | 93.41 | |
Ovarian cancer | IGROV1 | 105 | 106.3 | 104.3 | 100.53 | 110.36 |
OVCAR-3 | 109.2 | 113.9 | 111.8 | 104.47 | 106.37 | |
OVCAR-4 | 97.78 | 96.67 | 93.93 | 94.18 | 99.61 | |
OVCAR-5 | 104.8 | 102.9 | 101.1 | 105.8 | 102.63 | |
OVCAR-8 | 99.87 | 103.1 | 102.2 | 92.98 | 97.77 | |
NCI/ADR-RES | 102.4 | 102.1 | 103.1 | 108.87 | 102.13 | |
SK-OV-3 | 102.6 | 105.6 | 99.28 | 107.11 | 104.8 | |
Renal cancer | 786-0 | 98.32 | 100.2 | 100.1 | 100.59 | 104.72 |
A498 | 103.9 | 117 | 114.4 | 108.88 | 115.67 | |
ACHN | 98.77 | 92.38 | 89.61 | 99.89 | 99.4 | |
CAKI-1 | 92.91 | 82.3 | 78.52 | 99.75 | 89.58 | |
RXF 393 | 96.91 | 102 | 105.8 | 114.5 | 105.46 | |
SN 12C | 93.94 | 93.88 | 94.56 | 93.07 | 99.81 | |
TK-10 | 96.11 | 109.1 | 113.5 | 102.14 | 111.49 | |
Prostate cancer | PC-3 | 99.99 | 102.2 | 99.48 | 96.67 | 104.34 |
DU-145 | 104.9 | 104.6 | 103.3 | 105.71 | 104.85 | |
Breast cancer | MCF7 | 84.87 | 90.11 | 83.48 | 87.43 | 91.63 |
HS 578T | 98.14 | 96.97 | 92.76 | 93.19 | 100.05 | |
BT-549 | 103.5 | 117.7 | 112.2 | 117.25 | 115.87 | |
T-47D | 103.8 | 102.3 | 98.97 | 103.41 | 105.35 | |
MDA-MB-468 | 99.41 | 97.99 | 100 | 98.35 | 97.8 | |
Mean GP | 99.92 | 100.11 | 98.79 | 100.64 | 102.35 |
Compound | Anticancer Activity in One Dose (10 µM) | ||
---|---|---|---|
The Most Sensitive Cell Lines | GP | PGI | |
7a | MCF7 (Breast cancer) | 84.87 | 15.13 |
HL-60(TB) (Leukemia) | 86.23 | 13.77 | |
EKVX (Non-small cell lung cancer) | 89.44 | 10.56 | |
SK-MEL-5 (Melanoma) | 92.01 | 7.99 | |
CAKI-1 (Renal cancer) | 92.91 | 7.09 | |
7b | EKVX (Non-small cell lung cancer) | 80.73 | 19.27 |
CAKI-1 (Renal cancer) | 82.3 | 17.7 | |
HL-60(TB) (Leukemia) | 83.07 | 16.93 | |
UACC-62 (Melanoma) | 85.6 | 14.4 | |
LOX IMVI (Melanoma) | 87.19 | 12.81 | |
7c | EKVX (Non-small cell lung cancer) | 75.46 | 24.54 |
CAKI-1 (Renal cancer) | 78.52 | 21.48 | |
UACC-62 (Melanoma) | 80.81 | 19.19 | |
MCF7 (Breast cancer) | 83.48 | 16.52 | |
LOX IMVI (Melanoma) | 84.52 | 15.48 | |
7e | MCF7 (Breast cancer) | 87.43 | 12.57 |
EKVX (Non-small cell lung cancer) | 90.83 | 9.17 | |
LOX IMVI (Melanoma) | 92.19 | 7.81 | |
SK-MEL-5 (Melanoma) | 92.19 | 7.81 | |
SR (Leukemia) | 92.66 | 7.34 | |
7f | CAKI-1 (Renal cancer) | 89.58 | 10.42 |
EKVX (Non-small cell lung cancer) | 91.2 | 8.8 | |
MCF7 (Breast cancer) | 91.63 | 8.37 | |
K-562 (Leukemia) | 92.54 | 7.46 | |
SR (Leukemia) | 93.35 | 6.47 |
Panels | 7a | 7b | 7c | 7e | 7f | Imatinib * | Gefitinib * | Thalidomide * |
---|---|---|---|---|---|---|---|---|
Leukemia | 1.76 | 2.72 | 1.82 | −2.6 | 1.27 | 9 | 79.68 | 15.28 |
Non-small cell lung cancer | −2.94 | 0.01 | 2.07 | −0.7 | −3.85 | 15.68 | 63.97 | 0.06 |
Colon cancer | −3.05 | −4.5 | −1.39 | −1.3 | −6.43 | 5.34 | 52.19 | −0.27 |
CNS cancer | 2.36 | 1.74 | 2.02 | 2.41 | −0.74 | 5.8 | 46.13 | −4.95 |
Melanoma | 3.38 | 4.93 | 5.03 | 2.26 | 1.76 | −0.87 | 44.99 | −0.39 |
Ovarian cancer | −3.08 | −4.38 | −2.23 | −1.99 | −3.38 | −7.16 | 60.93 | 1.90 |
Renal cancer | 2.74 | 0.45 | 0.50 | −2.69 | −3.733 | 3.25 | 77.89 | −2.37 |
Prostate cancer | −2.46 | −3.40 | −1.41 | −1.19 | −4.59 | 12.5 | 59.60 | −8.60 |
Breast cancer | 2.06 | −0.99 | 2.25 | 0.07 | −2.35 | 12.15 | 52.88 | −2.04 |
S. No. | Compound | PDB: 1SA0 | PDB ID: 1SC7 | PDB ID: 3W2R | ||||
---|---|---|---|---|---|---|---|---|
Docking Score | Emodel Score | Docking Score | Emodel Score | Docking Score | Emodel Score | Interaction | ||
1 | 7a | −6.469 | −54.331 | −7.169 | −59.500 | −7.934 | −66.771 | H-bond (Lys745; 2.05 Å), π-π-stacking (Phe856; 5.21 Å) |
2 | 7b | −6.426 | −56.002 | −7.473 | −63.130 | −7.816 | −64.552 | H-bond (Lys745; 1.97 Å) |
3 | 7c | −6.480 | −57.825 | −7.318 | −64.802 | −7.558 | −64.096 | H-bond (Lys745; 2.04 Å) |
4 | 7d | −7.069 | −57.606 | −7.565 | −66.006 | −7.702 | −65.761 | H-bond (Lys745; 2.04 Å), π-π-stacking (Phe856; 5.48 Å) |
5 | 7e | −7.292 | −62.624 | −6.363 | −65.436 | −7.119 | −65.715 | H-bond (Lys745; 1.64 Å), H-bond (Asp855; 2.13 Å) |
6 | 7f | −5.830 | −54.813 | −7.306 | −63.183 | −8.644 | −65.599 | H-bond (Thr854 via H2O; 1.76 and 2.39 Å) |
S. No. | Compound | Free Radical Scavenging Activity IC50 (μM) |
---|---|---|
1 | 7a | 36.18 ± 0.31 |
2 | 7b | 39.22 ± 0.12 |
3 | 7c | 24.02 ± 0.29 |
4 | 7d | 16.05 ± 0.15 |
5 | 7e | 54.27 ± 0.49 |
6 | 7f | 15.99 ± 0.10 |
7 | Ascorbic acid | 14.02 ± 0.15 |
S. No. | Compound | % ABS | TPSA | HBA (<10) | HBD (<5) | NROTB | Log p (<5) | MW (500) | GI Absorption | Lipinski’s Violation (≤1) |
---|---|---|---|---|---|---|---|---|---|---|
1 | 7a | 81.91 | 78.51 | 4 | 2 | 4 | 1.74 | 299.26 | High | 0 |
2 | 7b | 81.51 | 78.51 | 3 | 2 | 4 | 1.92 | 315.71 | High | 0 |
3 | 7c | 81.51 | 78.51 | 3 | 2 | 4 | 2.03 | 360.16 | High | 0 |
4 | 7d | 78.73 | 87.74 | 4 | 2 | 5 | 1.93 | 311.29 | High | 0 |
5 | 7e | 81.51 | 78.51 | 3 | 2 | 4 | 1.94 | 315.71 | High | 0 |
6 | 7f | 78.73 | 87.74 | 4 | 2 | 5 | 2.05 | 311.29 | High | 0 |
S. No. | Compound | HEP | IMMUNO | MUTAGEN | CYTOTOX | LD50 (mg/Kg) | Toxicity Class |
---|---|---|---|---|---|---|---|
1 | 7a | + | − | − | − | 1000 | IV |
2 | 7b | + | − | − | − | 5000 | V |
3 | 7c | + | − | − | − | 1000 | IV |
4 | 7d | + | − | − | − | 5000 | V |
5 | 7e | + | − | − | − | 1500 | IV |
6 | 7f | + | − | − | − | 5000 | V |
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Afzal, O.; Ahsan, M.J. An Efficient Synthesis of 1-(1,3-Dioxoisoindolin-2-yl)-3-aryl Urea Analogs as Anticancer and Antioxidant Agents: An Insight into Experimental and In Silico Studies. Molecules 2024, 29, 67. https://doi.org/10.3390/molecules29010067
Afzal O, Ahsan MJ. An Efficient Synthesis of 1-(1,3-Dioxoisoindolin-2-yl)-3-aryl Urea Analogs as Anticancer and Antioxidant Agents: An Insight into Experimental and In Silico Studies. Molecules. 2024; 29(1):67. https://doi.org/10.3390/molecules29010067
Chicago/Turabian StyleAfzal, Obaid, and Mohamed Jawed Ahsan. 2024. "An Efficient Synthesis of 1-(1,3-Dioxoisoindolin-2-yl)-3-aryl Urea Analogs as Anticancer and Antioxidant Agents: An Insight into Experimental and In Silico Studies" Molecules 29, no. 1: 67. https://doi.org/10.3390/molecules29010067
APA StyleAfzal, O., & Ahsan, M. J. (2024). An Efficient Synthesis of 1-(1,3-Dioxoisoindolin-2-yl)-3-aryl Urea Analogs as Anticancer and Antioxidant Agents: An Insight into Experimental and In Silico Studies. Molecules, 29(1), 67. https://doi.org/10.3390/molecules29010067