Steroid-Functionalized Imidazolium Salts with an Extended Spectrum of Antifungal and Antibacterial Activity
Abstract
:1. Introduction
2. Results and Discussion
2.1. Synthesis of Imidazolium Salts
2.2. Antimicrobial Studies
2.3. Effect of ClogP Values on Antimicrobial Activity
2.4. Evaluation of the Hemolytic Activity of the Tested Compounds
2.5. Cytotoxicity Studies
3. Materials and Methods
3.1. General Remarks
3.2. General Procedure for the Synthesis of Imidazolium Salts
3.2.1. N-(3α-Hydroxy-5β-cholan-24-yl)-N′-propylimidazolium Iodide (3c)
3.2.2. N-Butyl-N′-(3α-hydroxy-5β-cholan-24-yl)imidazolium Iodide (3d)
3.2.3. N-(3α-Hydroxy-5β-cholan-24-yl)-N′-pentylimidazolium Iodide (3e)
3.2.4. N-Hexyl-N′-(3α-hydroxy-5β-cholan-24-yl)imidazolium Iodide (3f)
3.2.5. N-Heptyl-N′-(3α-hydroxy-5β-cholan-24-yl)imidazolium Iodide (3g)
3.2.6. N-(3α-Hydroxy-5β-cholan-24-yl)-N′-octylimidazolium Iodide (3h)
3.2.7. N-Dodecyl-N′-(3α-hydroxy-5β-cholan-24-yl)imidazolium Iodide (3i)
3.2.8. N-Hexadecyl-N′-(3α-hydroxy-5β-cholan-24-yl)imidazolium Iodide (3j)
3.2.9. N-(3-Oxo-23,24-dinorchol-4-en-22-yl)-N′-propylimidazolium Iodide (4c)
3.2.10. N-Butyl-N′-(3-oxo-23,24-dinorchol-4-en-22-yl)imidazolium Iodide (4d)
3.2.11. N-(3-Oxo-23,24-dinorchol-4-en-22-yl)-N′-pentylimidazolium Iodide (4e)
3.2.12. N-Hexyl-N′-(3-oxo-23,24-dinorchol-4-en-22-yl)imidazolium Iodide (4f)
3.2.13. N-Heptyl-N′-(3-oxo-23,24-dinorchol-4-en-22-yl)imidazolium Iodide (4g)
3.2.14. N-Octyl-N′-(3-oxo-23,24-dinorchol-4-en-22-yl)imidazolium Iodide (4h)
3.2.15. N-Dodecyl-N′-(3-oxo-23,24-dinorchol-4-en-22-yl)imidazolium Iodide (4i)
3.2.16. N-Hexadecyl-N′-(3-oxo-23,24-dinorchol-4-en-22-yl)imidazolium Iodide (4j)
3.3. Antimicrobial Activity
3.4. Hemocompatibility Studies
3.5. Cytotoxicity Studies
3.6. Statistical Analysis
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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Salt | Reaction Temperature | Reaction Time | Yield | Salt | Reaction Temperature | Reaction Time | Yield | Number of Carbon Atoms in the Alkyl Substituent |
---|---|---|---|---|---|---|---|---|
3a a | r.t. | 24 h | 83% | 4a a | r.t. | 20 h | 100% | 1 |
3b a | r.t. | 24 h | 64% | 4b a | r.t. | 20 h | 99% | 2 |
3c | 80 °C | 2 h | 74% | 4c | 80 °C | 0.25 h | 99% | 3 |
3d | 80 °C | 2 h | 71% | 4d | 80 °C | 1 h | 85% | 4 |
3e | 80 °C | 2 h | 72% | 4e | 80 °C | 1 h | 79% | 5 |
3f | 80 °C | 2 h | 72% | 4f | 80 °C | 1.5 h | 100% | 6 |
3g | 80 °C | 2 h | 70% | 4g | 80 °C | 3 h | 73% | 7 |
3h | 80 °C | 2 h | 74% | 4h | 100 °C | 2 h | 93% | 8 |
3i | 80 °C | 2 h | 64% | 4i | 100 °C | 1.5 h | 81% | 12 |
3j | 80 °C | 2 h | 55% | 4j | 100 °C | 2 h | 67% | 16 |
MIC (µg/mL) | |||||||
---|---|---|---|---|---|---|---|
Salt | S. aureus | B. cereus | E. coli | Salt | S. aureus | B. cereus | E. coli |
3a | 4 a | 32 a | 16 a | 4a | 32 a | 64 a | 16 a |
3b | 2 a | 16 a | 16 a | 4b | 16 a | 32 a | 8 a |
3c | 1 | 8 | 16 | 4c | 16 | 16 | 8 |
3d | 0.5 | 4 | 16 | 4d | 8 | 16 | 8 |
3e | 1 a | 4 a | 16 a | 4e | 4 a | 4 a | 4 a |
3f | 0.5 a | 2 a | 16 a | 4f | 2 a | 2 a | 4 a |
3g | 0.06 | 2 | 16 | 4g | 0.5 | 0.5 | 4 |
3h | 0.06 | 2 | 64 | 4h | 0.25 | 0.5 | 4 |
3i | 2 | 4 | 512 | 4i | 0.5 | 1 | 512 |
3j | 16 | 64 | 512 | 4j | 4 | 8 | 512 |
Ampicillin | 0.25–1 | 0.25–0.5 | 2–8 |
MIC (µg/mL) | ||||||
---|---|---|---|---|---|---|
Salt | C. albicans | A. niger | A. fumigatus | T. mentagrophytes | C. neoformans | M. canis |
3a | 0.25 a | 4 | 4 | 0.25 | 1 | 0.25 |
3b | 0.5 a | 1 | 1 | 0.5 | 1 | 0.25 |
3c | 0.25 | 16 | 8 | 2 | 2 | 0.25 |
3d | 0.5 | 16 | 8 | 2 | 4 | 0.25 |
3e | 0.5 a | 2 | 8 | 0.5 | 2 | 0.25 |
3f | 0.5 a | 4 | 8 | 0.5 | 4 | 0.25 |
3g | 0.5 | 8 | 16 | 1 | 8 | 0.5 |
3h | 1 | 8 | 16 | 2 | 8 | 1 |
3i | 8 | 64 | 16 | 4 | 32 | 2 |
3j | 32 | 64 | 64 | 32 | 64 | 16 |
4a | 2 a | 8 | 2 | 2 | 4 | 0.5 |
4b | 1 a | 2 | 4 | 2 | 2 | 0.25 |
4c | 0.06 | 16 | 8 | 2 | 2 | 0.5 |
4d | 0.06 | 8 | 8 | 1 | 2 | 0.25 |
4e | 2 a | 8 | 8 | 2 | 4 | 0.5 |
4f | 1 a | 2 | 8 | 1 | 2 | 0.25 |
4g | 0.5 | 8 | 16 | 1 | 4 | 0.25 |
4h | 0.5 | 4 | 16 | 1 | 4 | 0.25 |
4i | 0.5 | 4 | 4 | 1 | 4 | 0.25 |
4j | 8 | 16 | 32 | 4 | 32 | 2 |
Fluconazole | 0.5 | 16 | 64 | 64 | 4 | 32 |
Amphotericin B | 0.5 | 2 | 2 | 1 | 0.5 | 1 |
Voriconazole | 0.25 | 0.5 | 0.25 | 0.5 | 0.125 | 1 |
Salt | ClogP | Salt | ClogP |
---|---|---|---|
3a | 3.467 | 4a | 1.863 |
3b | 3.996 | 4b | 2.392 |
3c | 4.525 | 4c | 2.921 |
3d | 5.054 | 4d | 3.450 |
3e | 5.583 | 4e | 3.979 |
3f | 6.112 | 4f | 4.508 |
3g | 7.170 | 4g | 5.566 |
3h | 8.228 | 4h | 6.624 |
3i | 9.286 | 4i | 7.682 |
3j | 11.402 | 4j | 9.798 |
HC50 (µg/mL) | |||
---|---|---|---|
Salt | RBC | Salt | RBC |
3a | 265.1 | 4a | nd |
3b | 44.6 | 4b | nd |
3c | 54.7 | 4c | nd |
3d | 53.7 | 4d | nd |
3e | 39.9 | 4e | 401.4 |
3f | 42.3 | 4f | 43.9 |
3g | 12.2 | 4g | 57.6 |
3h | 541.6 | 4h | 33.8 |
3i | nd | 4i | 54.5 |
3j | nd | 4j | 367.3 |
IC50 (µg/mL) | Viability at MIC Value (%) | ||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|
Salt | CRL-1475 | THP-1 | Salt | CRL-1475 | THP-1 | Salt | CRL-1475 | THP-1 | Salt | CRL-1475 | THP-1 |
3a | 107.4 | nd | 4a | 469.0 | 562.9 | 3a | 100.6 ± 2.5 | 111.88 ± 22.5 | 4a | 100.6 ± 3.1 | 112.69 ± 2.59 |
3b | 113.9 | 205.3 | 4b | 524.2 | nd | 3b | 102.6 ± 1.5 | 122.4 ± 5.53 | 4b | 100.2 ± 2.3 | 130.51 ± 4.75 |
3c | 36.5 | 452.9 | 4c | 562.4 | 352.1 | 3c | 98.0 ± 4.3 | 95.11 ± 7.09 | 4c | 98.2 ± 1.4 | 105.38 ± 6.42 |
3d | 99.2 | 976.8 | 4d | 446.3 | 96.33 | 3d | 101.7 ± 2.3 | 99.82 ± 16.78 | 4d | 101.3 ± 2.0 | 109.39 ± 4.65 |
3e | 100.8 | 77.43 | 4e | 42.9 | 295.8 | 3e | 99.9 ± 2.6 | 123.59 ± 16.79 | 4e | 100.9 ± 1.5 | 71,49 ± 1.49 |
3f | 149.6 | nd | 4f | 717.7 | 313.2 | 3f | 102.3 ± 5.4 | 85.24 ± 16.19 | 4f | 99.8 ± 0.6 | 96.07 ± 13.97 |
3g | 134.4 | nd | 4g | 51.5 | 238.4 | 3g | 99.7 ± 3.4 | 85.24 ± 21.53 | 4g | 96.2 ± 1.9 | 87.07 ± 12.86 |
3h | 53.6 | 752.2 | 4h | 598.8 | 336.6 | 3h | 102.7 ± 2.9 | 119.57 ± 15.02 | 4h | 96.9 ± 2.2 | 106.68 ± 5.17 |
3i | 631.0 | nd | 4i | 457.7 | 713.9 | 3i | 80.5 ± 0.8 | 120.62 ± 17.80 | 4i | 100.2 ± 0.7 | 101.60 ± 13.22 |
3j | 841.1 | 451.4 | 4j | 282.3 | 853.4 | 3j | 101.26 ± 2.7 | 128.68 ± 14.53 | 4j | 81.3 ± 2.4 | 88.10 ± 19.77 |
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Malinowska, M.; Sawicka, D.; Niemirowicz-Laskowska, K.; Wielgat, P.; Car, H.; Hauschild, T.; Hryniewicka, A. Steroid-Functionalized Imidazolium Salts with an Extended Spectrum of Antifungal and Antibacterial Activity. Int. J. Mol. Sci. 2021, 22, 12180. https://doi.org/10.3390/ijms222212180
Malinowska M, Sawicka D, Niemirowicz-Laskowska K, Wielgat P, Car H, Hauschild T, Hryniewicka A. Steroid-Functionalized Imidazolium Salts with an Extended Spectrum of Antifungal and Antibacterial Activity. International Journal of Molecular Sciences. 2021; 22(22):12180. https://doi.org/10.3390/ijms222212180
Chicago/Turabian StyleMalinowska, Marta, Diana Sawicka, Katarzyna Niemirowicz-Laskowska, Przemysław Wielgat, Halina Car, Tomasz Hauschild, and Agnieszka Hryniewicka. 2021. "Steroid-Functionalized Imidazolium Salts with an Extended Spectrum of Antifungal and Antibacterial Activity" International Journal of Molecular Sciences 22, no. 22: 12180. https://doi.org/10.3390/ijms222212180