Exploring 4,7-Disubstituted Pyrimido[4,5-d]pyrimidines as Antiviral and Anticancer Agents
Abstract
1. Introduction
2. Results and Discussion
2.1. Chemistry
2.2. Biological Assays
2.2.1. Antiviral Activity
2.2.2. Anti-Proliferative Activity
3. Materials and Methods
3.1. General Information
3.2. Synthesis of Compounds 7a–7m
3.3. Biological Assays and Experiments
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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Compd. | Core | NR1R2 | Compd. | Core | NR1R2 |
---|---|---|---|---|---|
7a | 7h | ||||
7b | 7i | ||||
7c | 7j | ||||
7d | 7k | ||||
7e | 7l | ||||
7f | 7m | ||||
7g |
Antiviral Activity (EC50) | Cytotoxicity (CC50) | |||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
Compd. | HCoV | Influenza | RSV | HEL299 | Hep3B | MDCK | Hep2 | VeroE6 | ||||
229E | OC43 | NL63 | H1N1 | H3N2 | B | A Long | ||||||
HEL299 | Hep3B | MDCK | Hep2 | |||||||||
7a | 15.8 ± 0.9 | 27.7 ± 0.6 | >50 | >50 | >50 | >50 | >50 | >50 | >50 | >50 | >50 | >50 |
7b | 11.0 ± 2.7 | 34.7 ± 16.7 | >50 | >50 | >50 | >50 | >50 | >50 | >50 | >50 | >50 | >50 |
7c | >50 | >50 | >50 | >50 | >50 | >50 | >50 | >50 | >50 | >50 | >50 | >50 |
7d | >50 | >50 | >50 | >50 | >50 | >50 | >50 | >50 | >50 | >50 | >50 | >50 |
7e | 20.6 ± 0.3 | >50 | >50 | >50 | >50 | >50 | >50 | >50 | >50 | >50 | >50 | >50 |
7f | 3.9 ± 2.9 | 37.3 ± 15.1 | >50 | >50 | >50 | >50 | >50 | >50 | >50 | >50 | >50 | >50 |
7g | ≥30.5 | >50 | >50 | >50 | >50 | >50 | >50 | >50 | >50 | >50 | >50 | >50 |
7h | >50 | >50 | >50 | >50 | >50 | >50 | >50 | >50 | >50 | >50 | 29.6 ± 1.6 | >50 |
7i | 19.3 ±6.6 | ≥39.8 | >50 | >50 | >50 | >50 | >50 | >50 | 25.7 ± 0.6 | >50 | >50 | >50 |
7j | >50 | >50 | >50 | >50 | >50 | >50 | >50 | >50 | >50 | >50 | >50 | >50 |
7k | >50 | >50 | >50 | >50 | >50 | >50 | >50 | >50 | >50 | >50 | >50 | >50 |
7l | >50 | >50 | >50 | >50 | >50 | >50 | >50 | >50 | >50 | >50 | >50 | >50 |
7m | >50 | >50 | >50 | >50 | >50 | >50 | >50 | >50 | >50 | >50 | >50 | >50 |
Erlotinib | 22.5 ± 10 | >100 | >100 | >100 | >100 | >100 | >100 | >100 | >100 | >100 | >100 | >100 |
WZ4002 | 41.8 ± 9.8 | >100 | >100 | >100 | >100 | >100 | >100 | >100 | >100 | >100 | >100 | >100 |
OSI-420 | >100 | >100 | >100 | >100 | >100 | >100 | >100 | >100 | >100 | >100 | 41.0 ± 13.4 | >100 |
Icotinib | >100 | >100 | >100 | >100 | >100 | >100 | >100 | >100 | >100 | >100 | >100 | >100 |
CNX-2006 | 1.8 ± 0.2 | 2.2 ± 0.8 | >100 | >100 | >100 | >100 | >100 | 11.1 ± 1.0 | 4.3 ± 1.8 | 1.7 ± 0.4 | 11.7 ± 0.8 | 9.2 ± 1.1 |
CL-387785 | 0.4 ± 0.2 | 1.8 ± 0.4 | >100 | >100 | >100 | 4.5 ± 1.2 | >100 | >100 | 10.9 ± 0.6 | 7.1 ± 0.4 | 10.4 ± 1.9 | >100 |
Remdesivir | 0.05 ± 0.04 | 0.14 ± 0.007 | 0.14 ± 0.04 | - | - | - | 0.008 ± 0.001 | >10 | 8.1 ± 2.5 | - | 9.0 ± 1.3 | - |
Ribavirin | 38.9 ± 1.7 | 100.1 ± 19.0 | 39.9 ± 7.1 | 9.6 ± 1.0 | 7.2 ± 1.6 | 7.4 ± 0.8 | 35.9 ± 1.3 | >250 | 165.1 ± 20.2 | >250 | 88.8 ± 23.5 | >250 |
Zanamivir | - | - | - | 0.6 ± 0.3 | 3.0 ± 0.2 | 0.4 ± 0.01 | - | - | - | >100 | - | - |
Rimantadine | - | - | - | 1.7 ± 0.5 | 0.6 ± 0.07 | >100 | - | - | - | >100 | - | - |
Anti-Proliferative Activity (IC50) | ||||||||
---|---|---|---|---|---|---|---|---|
Compd. | LN-229 | Capan-1 | HCT-116 | NCI-H460 | DND-41 | HL-60 | K-562 | Z-138 |
7a | >100 | >100 | >100 | >100 | 57.9 ± 2.0 | >100 | 87.0 ± 1.3 | 58.9 ± 1.8 |
7b | >100 | >100 | >100 | >100 | 67.1 ± 4.7 | >100 | >100 | 62.6 ± 0.8 |
7c | >100 | >100 | >100 | >100 | >100 | >100 | >100 | >100 |
7d | >100 | >100 | >100 | >100 | 80.6 ± 10.2 | ≥71.0 | 61.3 ± 2.4 | 56.5 ± 1.2 |
7e | >100 | >100 | >100 | >100 | >100 | >100 | >100 | >100 |
7f | >100 | >100 | >100 | >100 | >100 | >100 | >100 | >100 |
7g | >100 | >100 | >100 | >100 | >100 | >100 | >100 | >100 |
7h | 97.1 ± 1.5 | >100 | >100 | >100 | 66.5 ± 0.8 | 79.1 ± 4.6 | 52.3 ± 4.4 | 52.6 ± 1.4 |
7i | >100 | >100 | >100 | >100 | 62.6 ± 0.1 | >100 | 51.8 ± 3.5 | 62.1 ± 0.8 |
7j | >100 | >100 | >100 | >100 | >100 | >100 | >100 | >100 |
7k | >100 | >100 | >100 | >100 | >100 | >100 | >100 | >100 |
7l | >100 | >100 | >100 | >100 | >100 | >100 | >100 | >100 |
7m | >100 | >100 | >100 | >100 | >100 | >100 | >100 | >100 |
Erlotinib | >100 | 18.6 ± 1.1 | >100 | >100 | >100 | 10.7 ± 0.1 | >100 | >100 |
WZ4002 | >100 | >100 | >100 | >100 | >100 | >100 | >100 | >100 |
OSI-420 | >100 | 41.7 ± 3.6 | >100 | >100 | >100 | >100 | >100 | >100 |
Icotinib | >100 | >100 | >100 | >100 | >100 | >100 | >100 | >100 |
CNX-2006 | 8.2 ± 1.2 | 1.7 ± 0.01 | 6.6 ± 0.7 | 8.7 ± 1.9 | 4.5 ± 0.2 | 3.8 ± 1.4 | 11.5 ± 0.06 | 2.6 ± 0.5 |
CL-387785 | 43.8 ± 6.7 | 0.1 ± 0.01 | 1.3 ± 1.1 | 2.8 ± 0.6 | 0.9 ± 0.2 | 1.9 ± 0.04 | 65.0 ± 0.2 | 0.2 ± 0.1 |
Etoposide | 3.0 ± 0.2 | 0.1 ± 0.03 | 1.4 ± 0.09 | 2.2 ± 0.8 | 0.1 ± 0.02 | 0.2 ± 0.01 | 6.0 ± 2.0 | 0.08 ± 0.03 |
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Georgiou, E.A.; Paraskevas, K.; Koutra, C.; Persoons, L.; Schols, D.; De Jonghe, S.; Kostakis, I.K. Exploring 4,7-Disubstituted Pyrimido[4,5-d]pyrimidines as Antiviral and Anticancer Agents. Molecules 2024, 29, 5549. https://doi.org/10.3390/molecules29235549
Georgiou EA, Paraskevas K, Koutra C, Persoons L, Schols D, De Jonghe S, Kostakis IK. Exploring 4,7-Disubstituted Pyrimido[4,5-d]pyrimidines as Antiviral and Anticancer Agents. Molecules. 2024; 29(23):5549. https://doi.org/10.3390/molecules29235549
Chicago/Turabian StyleGeorgiou, Eleftheria A., Konstantinos Paraskevas, Christina Koutra, Leentje Persoons, Dominique Schols, Steven De Jonghe, and Ioannis K. Kostakis. 2024. "Exploring 4,7-Disubstituted Pyrimido[4,5-d]pyrimidines as Antiviral and Anticancer Agents" Molecules 29, no. 23: 5549. https://doi.org/10.3390/molecules29235549
APA StyleGeorgiou, E. A., Paraskevas, K., Koutra, C., Persoons, L., Schols, D., De Jonghe, S., & Kostakis, I. K. (2024). Exploring 4,7-Disubstituted Pyrimido[4,5-d]pyrimidines as Antiviral and Anticancer Agents. Molecules, 29(23), 5549. https://doi.org/10.3390/molecules29235549