Coumarin-Annulated Ferrocenyl 1,3-Oxazine Derivatives Possessing In Vitro Antimalarial and Antitrypanosomal Potency
Abstract
:1. Introduction
2. Results
2.1. Chemistry
2.2. Biological Evaluation
2.3. Preliminary Mechanistic Studies
3. Materials and Methods
3.1. General Methods and Instrumentation
3.2. Synthesis of Target Compounds
3.2.1. General Procedure for Synthesis of Acyclic Derivatives 11a,b
3.2.2. General Procedure for Synthesis of Cyclic Coumarin-1,3-oxazin-2-one Derivatives 12a,b
3.2.3. Synthesis of 9-(2-((N,N-Dimethylamino)methyl)ferrocenemethyl)-9,10-dihydrochromeno[8,7-e][1,3]oxazin-2(8H)-one (13)
3.2.4. Synthesis of Acyclic Ferrocenyl Aminocoumarin-4-ols 15a–d
3.2.5. Synthesis of Ferrocenyl Coumarin-1,3-oxazin-2-one Derivatives 16a–d
3.2.6. Synthesis of 7-(2-((N,N-Dimethylamino)methyl)ferrocenemethyl)-7,8-dihydro-6H-[1,3]dioxolo[4’,5’:4,5]benzo[1,2-e][1,3]oxazine (19)
3.3. Biological Evaluation Assays
3.3.1. D7 P. falciparum Antiplasomidal Evaluation
3.3.2. T. b. Brucei 427 Antitrypanosomal Assay
3.3.3. Antiproliferative Assay against the HCC70 Triple-Negative Breast Cancer Cell Line
3.3.4. β-Hematin Binding Assay for Hemozoin Inhibition
3.3.5. UV-Vis DNA Titration Experiment for DNA Binding
3.3.6. Methylene Blue and Hoechst 33342 DNA Binding Assay for Competitive Intercalation or Minor Groove Binding
4. 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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Compound | IC50 (µM) | |
---|---|---|
3D7 P. falciparum | T. b. brucei 427 | |
11a | 9.1 | n.a. a |
11b | 1.7 | 9.4 |
12a | n.a. | n.a. |
12b | 7.3 | n.a. |
13 | 1.0 | n.d. b |
15a | n.a. | n.a. |
15b | n.a. | n.a. |
15c | 8.76 | 19.6 |
15d | 5.7 | 5.0 |
16a | 13.2 | n.a. |
16b | n.a. | n.a. |
16c | 12.55 | n.a. |
16d | n.a. | n.d. |
19 | 4.78 | n.d. |
20a c | 3.49 | n.a. |
20b c | 4.12 | 0.87 |
CQ | 0.03 | – |
Pentamidine | – | 0.014 |
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Mbaba, M.; Dingle, L.M.K.; Zulu, A.I.; Laming, D.; Swart, T.; de la Mare, J.-A.; Hoppe, H.C.; Edkins, A.L.; Khanye, S.D. Coumarin-Annulated Ferrocenyl 1,3-Oxazine Derivatives Possessing In Vitro Antimalarial and Antitrypanosomal Potency. Molecules 2021, 26, 1333. https://doi.org/10.3390/molecules26051333
Mbaba M, Dingle LMK, Zulu AI, Laming D, Swart T, de la Mare J-A, Hoppe HC, Edkins AL, Khanye SD. Coumarin-Annulated Ferrocenyl 1,3-Oxazine Derivatives Possessing In Vitro Antimalarial and Antitrypanosomal Potency. Molecules. 2021; 26(5):1333. https://doi.org/10.3390/molecules26051333
Chicago/Turabian StyleMbaba, Mziyanda, Laura M. K. Dingle, Ayanda I. Zulu, Dustin Laming, Tarryn Swart, Jo-Anne de la Mare, Heinrich C. Hoppe, Adrienne L. Edkins, and Setshaba D. Khanye. 2021. "Coumarin-Annulated Ferrocenyl 1,3-Oxazine Derivatives Possessing In Vitro Antimalarial and Antitrypanosomal Potency" Molecules 26, no. 5: 1333. https://doi.org/10.3390/molecules26051333