Chroman-4-One Derivatives Targeting Pteridine Reductase 1 and Showing Anti-Parasitic Activity
Abstract
:1. Introduction
2. Results and Discussion
2.1. Synthesis and Inhibitory Activity towards PTR1
2.2. Crystallographic Structures of LmPTR1 and TbPTR1 in Complex with Flavanones
2.3. Docking Studies and Crystal Structure Comparison
2.4. Biological Profile of Compounds 1–3
3. Materials and Methods
3.1. General Information
3.2. General Procedure for the Synthesis of Compounds 1–3
3.3. Computational Methodology
3.4. Protein Purification and Kinetic Profile Characterization
3.5. TbPTR1 and LmPTR1 Enzyme Assay
3.6. Crystallization
3.7. Data Collection, Structure Solution and Refinement
3.8. In Vitro Evaluation of Activity against L. infantum Intramacrophage Amastigotes
3.9. In Vitro Evaluation of Activity against T. brucei
3.10. Cytotoxicity Assessment against THP-1 Macrophages
3.11. hERG Assay
3.12. Cytochrome P450 1A2, 2C9, 2C19, 2D6 and 3A4 Assays
3.13. Cytotoxicity Assay against A549 and W1-38 Cells
3.14. Aurora B Kinase Assay
3.15. Assessment of Mitochondrial Toxicity
5. Conclusions
Supplementary Materials
Acknowledgments
Author Contributions
Conflicts of Interest
References
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- Sample Availability: Samples of the compounds are available from the authors.
Compound | IC50 TbPTR1 (μM) | IC50 LmPTR1 (μM) |
---|---|---|
1 | 31.0 | 57.0 |
2 | 133.0 | 35.0 |
3 | 82.0 | 36.0 |
1A | 4.3 | 12.5 |
2A | NI at 50 μM | NI at 50 μM |
3A | 38.0 | 35.0 |
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Di Pisa, F.; Landi, G.; Dello Iacono, L.; Pozzi, C.; Borsari, C.; Ferrari, S.; Santucci, M.; Santarem, N.; Cordeiro-da-Silva, A.; Moraes, C.B.; et al. Chroman-4-One Derivatives Targeting Pteridine Reductase 1 and Showing Anti-Parasitic Activity. Molecules 2017, 22, 426. https://doi.org/10.3390/molecules22030426
Di Pisa F, Landi G, Dello Iacono L, Pozzi C, Borsari C, Ferrari S, Santucci M, Santarem N, Cordeiro-da-Silva A, Moraes CB, et al. Chroman-4-One Derivatives Targeting Pteridine Reductase 1 and Showing Anti-Parasitic Activity. Molecules. 2017; 22(3):426. https://doi.org/10.3390/molecules22030426
Chicago/Turabian StyleDi Pisa, Flavio, Giacomo Landi, Lucia Dello Iacono, Cecilia Pozzi, Chiara Borsari, Stefania Ferrari, Matteo Santucci, Nuno Santarem, Anabela Cordeiro-da-Silva, Carolina B. Moraes, and et al. 2017. "Chroman-4-One Derivatives Targeting Pteridine Reductase 1 and Showing Anti-Parasitic Activity" Molecules 22, no. 3: 426. https://doi.org/10.3390/molecules22030426