Versatility of 7-Substituted Coumarin Molecules as Antimycobacterial Agents, Neuronal Enzyme Inhibitors and Neuroprotective Agents
Abstract
:1. Introduction
2. Results and Discussion
2.1. Medium Throughput Screen
2.2. Evaluation of Compound Activity in Quinolone Resistant Mycobacterium tuberculosis
2.3. Minimum Inhibitory Concentration Determination
2.4. Albumin Binding Assay
2.5. Cell Viability Assays
3. Materials and Methods
3.1. Compound Synthesis
3.2. Initial Medium Throughput In Vitro Activity Screen
3.3. Activity in Moxifloxacin Resistant M. tuberculosis
3.4. Minimum Inhibitory Concentration Determination
3.4.1. M. tuberculosis pMSP12:GFP in GAST-Fe Media
3.4.2. M. tuberculosis H37Rv:pCHERRY3 in 7H9+OADC
3.5. Bovine Serum Albumin Binding Assay
3.6. Chinese Hamster Ovary Cell Cytotoxicity Assays
3.7. Human Neuroblastoma SH-SY5Y Cell Viability Assays
3.7.1. Cell Line and Culture Conditions
3.7.2. SH-SY5Y Cytotoxicity Assays
3.7.3. MPP+-Induced Cytotoxicity in SH-SY5Y Cells
4. Conclusions
Acknowledgments
Author Contributions
Conflicts of Interest
References
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Sample Availability: Samples of the compounds CM1–CM19 are available from the authors. |
Series 1 | Series 2 | ||||||
---|---|---|---|---|---|---|---|
% M. tuberculosis Growth, Day 5 | |||||||
Number | X | R1 | R2 | R3 | 100 µM | 50 µM | 1 µM |
Series 1 | |||||||
CM12 ** | N | Br | CH3 | H | 3.93 | 4.35 | 95.23 |
CM14 ** | N | Br | CH3 | CN | 4.44 | 4.40 | 99.53 |
CM8 ** | CH | H | CH3 | Cl | 4.62 | 5.69 | 93.59 |
CM15 ** | N | Br | CF3 | H | 4.88 | 6.68 | 106.71 |
CM11 * | N | Br | H | H | 4.46 | 7.05 | 95.18 |
CM9 * | CH | H | CH3 | CN | 6.19 | 7.75 | 92.82 |
CM7 * | CH | H | CH3 | H | 8.18 | 29.50 | 95.10 |
CM6 | CH | H | H | H | 15.43 | 52.71 | 98.19 |
CM13 * | N | Br | CH3 | Cl | 32.06 | 42.47 | 97.03 |
Series 2 | |||||||
CM17 * | H | CH3 | H | 19.81 | 28.65 | 97.59 | |
CM2 * | Br | CH3 | H | 33.16 | 40.86 | 89.98 | |
CM4 * | Br | CH3 | CN | 33.52 | 44.60 | 95.27 | |
CM5 | Br | CF3 | H | 56.09 | 65.04 | 106.87 | |
CM19 | H | CH3 | CN | 55.44 | 66.92 | 98.28 | |
CM16 | H | H | H | 50.66 | 72.70 | 97.53 | |
CM1 | Br | H | H | 63.63 | 79.77 | 96.28 | |
CM18 | H | CH3 | Cl | 75.52 | 87.91 | 97.30 | |
CM3 | Br | CH3 | Cl | 92.86 | 96.11 | 97.82 |
Compound | GFP GAST-Fe | mCHERRY—7H9+OADC | ||||
---|---|---|---|---|---|---|
MIC90 (µM) | MIC99 (µM) | MIC90 (µM) | St. Dev. | MIC99 (µM) | St. Dev. | |
CM8 | 19.6 | 25.2 | 40.55 | 1.16 | 44.15 | 1.37 |
CM12 | 14 | 29.7 | 40.89 | 0.06 | 50.40 | 8.96 |
CM14 | 16.7 | 28 | 45.22 | 3.04 | 54.46 | 9.58 |
CM15 | 3.2 | 8.31 | 43.78 | 1.46 | 57.17 | 10.05 |
Compound | T (°C) | λEx (nm) | λEm (nm) | ksv (mol L−1) | kq (mol L−1 S−1) | R2 |
---|---|---|---|---|---|---|
CM14 | 22 | 350 a 350 b | 395 a 400 b | 3.80 × 105 | 2.63 × 1014 | 0.9780 |
CM15 | 22 | 335 a 335 b | 415 a 415 b | 4.88 × 105 | 2.00 × 1014 | 0.9927 |
CM | CC50 µM CHO | SI GFP a | SI mCHERRY b | CC 50% SH-SY5Y c | MAO-A IC50 µM d | MAO-B IC50 µM d | AChE IC50 µM d | BuChE IC50 µM d |
---|---|---|---|---|---|---|---|---|
CM8 | 33.0 | 1.31 | 0.75 | ND | n.a. | 0.29 | 31.30 | 1.27 |
CM9 | ND | ND | ND | 10–50 | n.a. | 0.30 | 9.10 | 5.90 |
CM12 | 15.5 | 0.52 | 0.31 | ND | n.a. | 3.60 | 12.8 | 9.70 |
CM14 | 41.2 | 1.47 | 0.76 | 50–100 | n.a. | 1.41 | 38.5 | 13.3 |
CM15 | 26.3 | 3.16 | 0.46 | 10–50 | n.a. | 5.64 | >100 | >100 |
Emetine | 0.06 | ND | ND | ND | ND | ND | ND | ND |
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Kapp, E.; Visser, H.; Sampson, S.L.; Malan, S.F.; Streicher, E.M.; Foka, G.B.; Warner, D.F.; Omoruyi, S.I.; Enogieru, A.B.; Ekpo, O.E.; et al. Versatility of 7-Substituted Coumarin Molecules as Antimycobacterial Agents, Neuronal Enzyme Inhibitors and Neuroprotective Agents. Molecules 2017, 22, 1644. https://doi.org/10.3390/molecules22101644
Kapp E, Visser H, Sampson SL, Malan SF, Streicher EM, Foka GB, Warner DF, Omoruyi SI, Enogieru AB, Ekpo OE, et al. Versatility of 7-Substituted Coumarin Molecules as Antimycobacterial Agents, Neuronal Enzyme Inhibitors and Neuroprotective Agents. Molecules. 2017; 22(10):1644. https://doi.org/10.3390/molecules22101644
Chicago/Turabian StyleKapp, Erika, Hanri Visser, Samantha L. Sampson, Sarel F. Malan, Elizabeth M. Streicher, Germaine B. Foka, Digby F. Warner, Sylvester I. Omoruyi, Adaze B. Enogieru, Okobi E. Ekpo, and et al. 2017. "Versatility of 7-Substituted Coumarin Molecules as Antimycobacterial Agents, Neuronal Enzyme Inhibitors and Neuroprotective Agents" Molecules 22, no. 10: 1644. https://doi.org/10.3390/molecules22101644
APA StyleKapp, E., Visser, H., Sampson, S. L., Malan, S. F., Streicher, E. M., Foka, G. B., Warner, D. F., Omoruyi, S. I., Enogieru, A. B., Ekpo, O. E., Zindo, F. T., & Joubert, J. (2017). Versatility of 7-Substituted Coumarin Molecules as Antimycobacterial Agents, Neuronal Enzyme Inhibitors and Neuroprotective Agents. Molecules, 22(10), 1644. https://doi.org/10.3390/molecules22101644