Indoline-6-Sulfonamide Inhibitors of the Bacterial Enzyme DapE
Abstract
:1. Introduction
2. Results
2.1. Overview and Regiochemistry
2.2. Molecular Docking Experiments
2.3. Chemistry
2.4. DapE Enzyme Inhibition and Structure–Activity Relationships
3. Summary
4. Materials and Methods
4.1. General Experimental Methods
4.2. Molecular Docking Protocol
4.3. DapE Enzyme Inhibition
4.4. Protein Expression and Purification
4.5. Synthetic Organic Chemistry
4.5.1. 1-Acetyl-5-Chloroindoline (7b)
4.5.2. 1-Acetyl 5-Bromoindoline-6-Sulfonyl Chloride (8a)
4.5.3. 1-Acetyl-5-Chloroindoline-6-Sulfonyl Chloride (8b)
4.5.4. General Procedure for the Synthesis of N-acetyl 5-Bromo-6-Sulfonamide Indolines (4, 9 and 10)
4.5.5. 1-Acetyl-5-Bromo-N-Isopentylindoline-6-Sulfonamide (4)
4.5.6. 1-Acetyl-5-Bromo-N-Isobutylindoline-6-Sulfonamide (9a)
4.5.7. 1-Acetyl-5-Bromo-N-Cyclohexylindoline-6-Sulfonamide (9b)
4.5.8. 1-Acetyl-N-Benzyl-5-Bromoindoline-6-Sulfonamide (9c)
4.5.9. 1-Acetyl-5-Bromo-N-(Tert-Butyl)Indoline-6-Sulfonamide (9d)
4.5.10. 1-Acetyl-5-Bromoindolin-6-(Sulfonyl Glycine Methyl Ester) (9e)
4.5.11. Methyl 3-((1-Acetyl-5-Bromoindoline)-6-Sulfonamido)Propanoate (9f)
4.5.12. Methyl ((1-Acetyl-5-Bromoindolin-6-yl)Sulfonyl)Valinate (9g)
4.5.13. Methyl ((1-Acetyl-5-Bromoindolin-6-yl)Sulfonyl)-L-Phenylalaninate (9h)
4.5.14. 1-Acetyl-5-Bromo-6-(Piperidin-1-Sulfonyl) Indoline (9i)
4.5.15. 1-Acetyl-5-Bromo-6-(Pyrrolidin-1-Sulfonyl) Indoline (9j)
4.5.16. 1-Acetyl-5-Bromo-6-(Indolin-1-Sulfonyl) Indoline (9k)
4.5.17. 1-Acetyl-5-Bromo-N,N-Dipropylindoline-6-Sulfonamide (9l)
4.5.18. 1-Acetyl-5-Bromo-N,N-bis(2-Methoxyethyl)Indoline-6-Sulfonamide (9m)
4.5.19. 1-Acetyl-5-Bromo-N,N-Diethylindoline-6-Sulfonamide (9n)
4.5.20. 1-Acetyl-5-Chloro-N-Isopentylindoline-6-Sulfonamide (10a)
4.5.21. 1-Acetyl-5-Chloro-N-Cyclohexylindoline-6-Sulfonamide (10b)
4.5.22. 1-(5-Chloro-6-(Piperidin-1-Ylsulfonyl)Indolin-1-yl)Ethan-1-One (10c)
4.5.23. 1-(5-Chloro-6-(Pyrrolidin-1-Ylsulfonyl)Indolin-1-yl)ethan-1-One (10d)
4.5.24. 1-Acetyl-5-Chloro-N,N-Dipropylindoline-6-Sulfonamide (10e)
4.5.25. 1-Acetyl-5-Chloro-N,N-bis(2-Methoxyethyl)Indoline-6-Sulfonamide (10f)
5. Conclusions
6. Patents
Supplementary Materials
Author Contributions
Funding
Conflicts of Interest
References
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0 | X | R | MW | clogP | mp (°C) | IC50 (μM) or % Inhibition a |
---|---|---|---|---|---|---|
4 | Br | 389.3 | 2.79 | 190–191 | 42% at 200 μM | |
9a | Br | 374.0 | 2.26 | 225.4–226.1 | 20% at 200 μM | |
9b | Br | 400.0 | 2.84 | 226–228 | 162 | |
9c | Br | 408.0 | 2.57 | 205–208 | 56% at 200 μM | |
9d | Br | 374.0 | 2.04 | 235.7–236.1 | 39% at 100 μM | |
9e | Br | 390.0 | 0.79 | 179–182 | 17% at 200 μM | |
9f | Br | 404.0 | 1.1 | 190–193 | 118 | |
9g | Br | 432.0 | 2.0 | 190.9–191.7 | 82 | |
9h | Br | 480.0 | 2.5 | 184.0–184.8 | 61% at 200 μM | |
9i | Br | 386.0 | 2.1 | 212–214 | 133 | |
9j | Br | 372.0 | 1.6 | 238–240 | 97 | |
9k | Br | 420.0 | 2.6 | 215–218 | 86 | |
9l | Br | 402.1 | 3.0 | 118–120 | 5% at 20 μM, insol. at 200 μM | |
9m | Br | 434.1 | 1.5 | 110–111 | 26% at 100 μM | |
9n | Br | 374.0 | 2.0 | 195–196 | 99 | |
10a | Cl | 344.1 | 2.8 | 179.1–180.4 | 54 | |
10b | Cl | 356.1 | 2.9 | 230.0–230.5 | 58% at 200 μM | |
10c | Cl | 342.1 | 2.2 | 199.7–201.4 | 44 | |
10d | Cl | 328.1 | 1.6 | 199.7–200.4 | 172 | |
10e | Cl | 358.1 | 3.1 | 118–120 | 88 | |
10f | Cl | 390.1 | 1.5 | 93.2–94.4 | >200 |
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Reidl, C.T.; Heath, T.K.; Darwish, I.; Torrez, R.M.; Moore, M.; Gild, E.; Nocek, B.P.; Starus, A.; Holz, R.C.; Becker, D.P. Indoline-6-Sulfonamide Inhibitors of the Bacterial Enzyme DapE. Antibiotics 2020, 9, 595. https://doi.org/10.3390/antibiotics9090595
Reidl CT, Heath TK, Darwish I, Torrez RM, Moore M, Gild E, Nocek BP, Starus A, Holz RC, Becker DP. Indoline-6-Sulfonamide Inhibitors of the Bacterial Enzyme DapE. Antibiotics. 2020; 9(9):595. https://doi.org/10.3390/antibiotics9090595
Chicago/Turabian StyleReidl, Cory T., Tahirah K. Heath, Iman Darwish, Rachel M. Torrez, Maxwell Moore, Elliot Gild, Boguslaw P. Nocek, Anna Starus, Richard C. Holz, and Daniel P. Becker. 2020. "Indoline-6-Sulfonamide Inhibitors of the Bacterial Enzyme DapE" Antibiotics 9, no. 9: 595. https://doi.org/10.3390/antibiotics9090595