Efficient Two-Step Synthesis of Novel Pyrimido[4,5-d] Pyrimidines with Potent Neuroprotective, Antioxidant, and Aβ Anti-Aggregation Properties
Abstract
:1. Introduction
2. Results
2.1. Synthesis
2.2. Biological Evaluation
2.2.1. In Cellulo Evaluation of the Neuroprotective Activity of Compounds 4a–k
2.2.2. Antioxidant Analysis
2.2.3. Inhibition of Self-Induced Aβ1–42 Aggregation by Compounds 4g, 4i and 4j
2.2.4. ADME Studies
3. Materials and Methods
3.1. Synthesis of Compounds 2a–k
3.2. Synthesis of Compounds 4a–k
3.3. Biological Evaluation
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Data Availability Statement
Conflicts of Interest
References
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Compound | R1 | R2 | R3 | R4 | R5 | R6 | Yield (%) |
---|---|---|---|---|---|---|---|
4a | CH3 | H | H | H | H | H | 57 |
4b | C2H5 | H | H | H | H | H | 50 |
4c | CH3 | C2H5 | H | H | H | H | 35 |
4d | CH3 | H | CH3 | H | H | H | 16 |
4e | CH3 | CH3 | CH3 | H | H | H | 20 |
4f | CH3 | CH3 | H | H | H | H | 50 |
4g | CH3 | CH3 | H | H | CH3 | H | 28 |
4h | CH3 | C2H5 | H | H | CH3 | H | 30 |
4i | CH3 | CH3 | H | H | Cl | H | 22 |
4j | CH3 | C2H5 | H | OCH3 | OCH3 | H | 20 |
4k | CH3 | H | H | OCH3 | H | OCH3 | 47 |
Compound | Neuroprotection (%) against H2O2 a at 0.1, 1 and 5µM | ORAC c (TE) | ||
---|---|---|---|---|
0.1 µM | 1 µM | 5 µM | ||
4a | - b | - b | - b | 0.07 ± 0.00 |
4b | 6.17 ± 0.01 | 4.95 ± 0.01 | 14.66 ± 0.04 | - b |
4c | 6.96 ± 0.02 | 3.09 ± 0.2 | 8.64 ± 0.05 | 0.24 ± 0.02 |
4d | 9.40 ± 0.01 | - b | - b | 0.14 ± 0.01 |
4e | - b | 34.00 ± 0.09 * | 8.45 ± 0.2 | 0.17 ± 0.01 |
4f | 4.75 ± 0.01 | 6.98 ± 0.02 | 24.30 ± 0.02 * | 0.19 ± 0.02 |
4g | 47.03 ± 0.12 ** | 68.06 ± 0.22 ** | 77.55 ± 0.21 ** | 0.24 ± 0.02 |
4h | 66.13 ± 0.17 ** | 38.77 ± 0.07 ** | 26.12 ± 0.16 ** | - b |
4i | 68.35 ± 0.23 ** | 117.89 ± 0.04 *** | 94.54 ± 0.33 *** | 0.34 ± 0.01 |
4j | 66.94 ± 0.23 ** | 45.89 ± 0187 ** | 11.14 ± 0.15 | 1.64 ± 0.02 |
4k | 0.13 ± 0.01 | - b | - b | - b |
Trolox | - d | - d | - d | 0.99 ± 0.01 |
Melatonin | - d | - d | - d | 2.45 ± 0.09 |
Compound | Molweight (g/mol) | CLogP | H-Acceptors | H-Donors | Topological Polar Surface Area (Å2) | hERG Inhibition |
---|---|---|---|---|---|---|
4a | 312.375 | 3.8793 | 4 | 0 | 51.56 | low_risk |
4b | 326.402 | 4.2949 | 4 | 0 | 51.56 | low_risk |
4c | 340.429 | 4.6928 | 4 | 0 | 51.56 | medium_risk |
4d | 326.402 | 4.2232 | 4 | 0 | 51.56 | medium_risk |
4e | 340.429 | 4.6211 | 4 | 0 | 51.56 | medium_risk |
4f | 326.402 | 4.2772 | 4 | 0 | 51.56 | low_risk |
4g | 340.429 | 4.6211 | 4 | 0 | 51.56 | medium_risk |
4h | 354.456 | 5.0367 | 4 | 0 | 51.56 | medium_risk |
4i | 360.847 | 4.8832 | 4 | 0 | 51.56 | medium_risk |
4j | 400.481 | 4.5528 | 6 | 0 | 70.02 | medium_risk |
4k | 372.427 | 3.7393 | 6 | 0 | 70.02 | medium_risk |
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Ben Ameur, G.; Maalej, E.; Martin, H.; Jacquinot, A.-S.; Barbanneau, N.; Bernard, P.J.; Marco-Contelles, J.; Chabchoub, F.; Ismaili, L. Efficient Two-Step Synthesis of Novel Pyrimido[4,5-d] Pyrimidines with Potent Neuroprotective, Antioxidant, and Aβ Anti-Aggregation Properties. Chemistry 2024, 6, 695-705. https://doi.org/10.3390/chemistry6040041
Ben Ameur G, Maalej E, Martin H, Jacquinot A-S, Barbanneau N, Bernard PJ, Marco-Contelles J, Chabchoub F, Ismaili L. Efficient Two-Step Synthesis of Novel Pyrimido[4,5-d] Pyrimidines with Potent Neuroprotective, Antioxidant, and Aβ Anti-Aggregation Properties. Chemistry. 2024; 6(4):695-705. https://doi.org/10.3390/chemistry6040041
Chicago/Turabian StyleBen Ameur, Ghada, Emna Maalej, Helene Martin, Anne-Sophie Jacquinot, Nadine Barbanneau, Paul J. Bernard, José Marco-Contelles, Fakher Chabchoub, and Lhassane Ismaili. 2024. "Efficient Two-Step Synthesis of Novel Pyrimido[4,5-d] Pyrimidines with Potent Neuroprotective, Antioxidant, and Aβ Anti-Aggregation Properties" Chemistry 6, no. 4: 695-705. https://doi.org/10.3390/chemistry6040041