In Vitro Anti-Candida Activity and Action Mode of Benzoxazole Derivatives
Abstract
:1. Introduction
2. Results
2.1. Synthesis of Benzoxazoles
Lp. | Benzoxazole | 4, ArCOCH2X a | Ketone (%) | Alcohol (%) | ||
---|---|---|---|---|---|---|
1 | 1 | C6H5 | 5a [24,25,26,27] | 98 | 8a | − b |
2 | 1 | 4-FC6H4 | 5b | 91 | 8b | 88 |
3 | 1 | 4-ClC6H4 | 5c [24] | 95 | 8c | 91 |
4 | 1 | 4-BrC6H4 | 5d [24,27] | 96 | 8d | 95 |
5 | 1 | 2,4-F2C6H3 | 5e | 88 | 8e | 57 |
6 | 1 | 2,4-Cl2C6H3 | 5f | 87 | 8f | 61 |
7 | 1 | 2,5-Cl2C6H3 | 5g | 91 | 8g | 37 c |
8 | 1 | 3,4-Cl2C6H3 | 5h | 67 | 8h | 73 |
9 | 1 | 2,3,4-Cl3C6H2 | 5i | 92 | 8i | 87 |
10 | 1 | 2,4,5-Cl3C6H2 | 5j | 91 | 8j | 89 |
11 | 1 | 2,4,6-Cl3C6H2 | 5k | 64 | 8k | − d |
12 | 2 | C6H5 | 6a | 71 | 9a | 39 c,e |
13 | 2 | 4-FC6H4 | 6b | 55 | 9b | 36 c,e |
14 | 3 | C6H5 | 7a | 53 | 10a | 33 c,e |
15 | 3 | 4-FC6H4 | 7b | 39 | 10b | − e |
2.2. Anti-Candida Activity of Benzoxazoles
2.3. Assessment of the Cytotoxicity against the Mammalian Cell Lines
2.4. Estimation of the Ergosterol Content in the Benzoxazole-Treated Candida Blastoconidia
2.5. Cell Death Assessment Using Flow Cytometry
2.6. Efflux Study in the Benzoxazole-Treated C. albicans Cells
2.7. Determination of Antifungal Activity of Benzoxazole Derivatives in the Presence of Exogenous Ergosterol
2.8. Anti-Candida Effect of Benzoxazole Derivatives Combined with Amphotericin B (AmB). FIC Index Calculation
3. Discussion
4. Materials and Methods
4.1. Synthesis of Benzoxazoles
4.2. Synthesis of 2-amino-4-bromophenol
4.3. Synthesis of 2-amino-4,6-dibromophenol
4.4. General Procedure for Synthesis of Ketones 5–7
4.5. General Procedure for Synthesis of Alcohols 8
4.6. Fungal Strains and Culture Conditions
4.7. In Vitro Antifungal Activity
4.8. Cytotoxicity Assay In Vitro
4.9. Ergosterol Estimation Assay Using Spectrophotometry and HPLC
4.10. Cytometric Analysis of C. albicans Cell Death Type
4.11. Examination of Rhodamine 123 Efflux in the C. albicans SC5314 Treated with Benzoxazole Derivatives
4.12. Antifungal Studies Using Exogenous Ergosterol
4.13. Determination of Antifungal Effect of Benzoxazole Derivatives Combined with Amphotericin B (AmB). FIC Index Calculation
4.14. Statistical Analysis
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Sample Availability
References
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Comp. | Conc. (μg/mL) | |||||
---|---|---|---|---|---|---|
16 | 8 | 4 | 2 | 1 | 0.5 | |
5a | 11.7 ± 3.8 | 10.0 ± 2.3 | 10.4 ± 4.7 | 8.8 ± 2.4 | 8.1 ± 0.6 | 7.8 ± 1.1 |
5b | 99.3 ± 4.3 | 86.9 ± 10.6 | 80.3 ± 13.4 | 82.9 ± 1.5 | 72.0 ± 21.9 | 68.7 ± 16.8 |
5c | 96.4 ± 0.6 | 85.3 ± 16.6 | 85.7 ± 16.6 | 79.9 ± 7.3 | 79.4 ± 4.3 | 57.6 ± 16.4 |
5d | 100.3 ± 3.2 ** | 96.4 ± 2.6 | 96.1 ± 6.6 | 76.5 ± 10.0 | 74.9 ± 9.5 | 71.0 ± 15.0 |
5e | 27.7 ± 3.3 | 10.9 ± 2.9 | 10.9 ± 3.5 | 10.0 ± 2.5 | 9.3 ± 3.1 | 7.2 ± 0.1 |
5f | 93.1 ± 8.8 * | 87.6 ± 2.2 | 87.9 ± 11.3 | 82.1 ± 2.6 | 80.0 ± 1.3 | 68.2 ± 20.3 |
5g | 73.8 ± 0.4 | 72.9 ± 0.6 | 70.9 ± 2.6 | 71.8 ± 5.1 | 69.4 ± 0.6 | 68.8 ± 0.6 |
5h | 98.55 ± 0.26 | 98.52 ± 0.20 | 99.27 ± 0.07 | 98.99 ± 0.15 | 98.98 ± 0.14 | 98.33 ± 0.26 |
5i | 78.7 ± 2.1 | 75.6 ± 1.6 | 73.3 ± 2.7 | 73.6 ± 3.5 | 73.3 ± 20.2 | 66.3 ± 10.9 |
5j | 17.6 ± 0.8 | 12.5 ± 3.6 | 9.1 ± 0.6 | 8.0 ± 0.2 | 8.1 ± 0.5 | 8.2 ± 0.5 |
5k | 76.6 ± 1.2 * | 74.5 ± 1.7 | 73.5 ± 0.8 | 72.5 ± 27.0 | 70.0 ± 14.3 | 65.8 ± 10.2 |
6a | 79.7 ± 3.1 * | 74.9 ± 1.2 | 74.9 ± 2.4 | 72.8 ± 15.2 | 70.6 ± 8.0 | 70.7 ± 0.2 |
6b | 60.9 ± 12.9 | 45.0 ± 8.3 | 41.3 ± 9.7 | 30.8 ± 7.2 | 5.0 ± 1.1 | 2.0 ± 1.1 |
7a | 79.5 ± 12.5 * | 45.0 ± 16.1 | 44.2 ± 8.2 | 42.0 ± 20.1 | 25.2 ± 4.0 | 17.7 ± 3.1 |
7b | 65.3 ± 21.8 | 39.7 ± 9.3 | 22.3 ± 4.3 | 31.6 ± 17.6 | 18.6 ± 0.2 | 5.0 ± 1.1 |
8b | 98.32 ± 0.23 | 98.47 ± 0.21 | 98.18 ± 0.27 | 98.84 ± 0.18 | 98.55 ± 0.23 | 98.59 ± 0.16 |
8c | 8.7 ± 1.9 | 8.8 ± 1.9 | 8.4 ± 1.1 | 7.5 ± 0.5 | 7.4 ± 0.5 | 6.9 ± 0.0 |
8d | 7.0 ± 1.5 | 6.5 ± 0.6 | 6.3 ± 0.1 | 6.4 ± 0.1 | 6.5 ± 0.0 | 6.4 ± 0.0 |
8e | 98.53 ± 0.12 | 99.43 ± 0.07 | 99.32 ± 0.06 | 98.78 ± 0.10 | 99.17 ± 0.08 | 99.24 ± 0.10 |
8f | 7.6 ± 1.3 | 6.8 ± 0.3 | 6.6 ± 0.0 | 6.9 ± 0.2 | 6.8 ± 0.2 | 6.6 ± 0.0 |
8h | 14.1 ± 3.9 | 8.1 ± 0.2 | 8.8 ± 0.9 | 8.7 ± 0.5 | 8.1 ± 0.1 | 7.8 ± 0.1 |
8i | 10.9 ± 4.7 | 8.9 ± 1.9 | 7.1 ± 0.1 | 7.1 ± 0.1 | 6.8 ± 0.0 | 6.9 ± 0.1 |
8j | 98.29 ± 0.02 | 99.28 ± 0.16 | 98.79 ± 0.12 | 98.38 ± 0.22 | 98.40 ± 0.04 | 98.41 ± 0.20 |
Candida Isolate | Comp. (μg/mL) | % Cell Growth Inhibition (Mean ± SD) | |||||
---|---|---|---|---|---|---|---|
16 | 8 | 4 | 2 | 1 | 0.5 | ||
C. albicans | 5d | 52.0 ± 15.7 | 44.1 ± 9.1 | 40.6 ± 14.9 | 21.4 ± 4.4 | 20.4 ± 10.3 | 16.0 ± 3.3 |
5i | 55.7 ± 13.1 | 42.0 ± 12.2 | 22.9 ± 12.2 | 10.5 ± 2.9 | 6.5 ± 2.9 | 4.6 ± 1.2 | |
5k | 64.2 ± 10.6 * | 56.5 ± 16.2 | 44.4 ± 14.3 | 40.0 ± 14.6 | 1.7 ± 0.4 | 1.0 ± 0.4 | |
6a | 88.0 ± 9.7 * | 69.4 ± 6.5 | 48.0 ± 6.6 | 27.9 ± 4.3 | 26.5 ± 9.3 | 6.9 ± 3.0 | |
C. glabrata | 5d | 38.3 ± 3.8 | 26.2 ± 4.6 | 16.6 ± 4.2 | 10.1 ± 2.1 | 14.5 ± 1.0 | 9.2 ± 0.8 |
5i | 53.0 ± 3.5 | 34.4 ± 3.0 | 14.4 ± 2.8 | 13.2 ± 1.4 | 11.6 ± 2.1 | 7.5 ± 1.4 | |
5k | 35.0 ± 5.1 | 19.1 ± 1.7 | 25.5 ± 2.5 | 26.5 ± 3.4 | 3.5 ± 0.5 | 12.3 ± 1.4 | |
6a | 27.0 ± 6.1 | 23.6 ± 3.3 | 10.4 ± 1.3 | 7.0 ± 0.5 | 3.0 ± 0.5 | 1.0 ± 0.5 |
Cell Line ATCC | Comp. [µg/mL] | % Cytotoxicity (Mean ± SD) | |||||||||
---|---|---|---|---|---|---|---|---|---|---|---|
512 | 256 | 128 | 64 | 32 | 16 | 8 | 4 | 2 | 1 | ||
Kidney Vero E6 | 5d | - | 61.3 ± 1.0 | 18.4 ± 0.4 | 17.0 ± 1.0 | 8.7 ± 0.2 | 6.1 ± 0.3 | 4.4 ± 0.2 | 3.6 ± 0.2 | 3.4 ± 0.1 | 2.1 ± 0.1 |
6a | - | 60.2 ± 3.3 | 17.2 ± 0.4 | 10.1 ± 0.5 | 5.4 ± 0.3 | 5.0 ± 0.2 | 2.9 ± 0.1 | 0.1 ± 0.0 | 0.0 ± 0.0 | 0.0 ± 0.0 | |
7a | - | 63.8 ± 8.7 | 14.4 ± 0.5 | 9.1 ± 0.7 | 5.4 ± 0.4 | 4.2 ± 0.1 | 1.6 ± 0.1 | 1.4 ± 0.1 | 0.9 ± 0.0 | 0.0 ± 0.0 | |
Pulmonary Fibroblasts MRC-5 | 5a | 40.64 ± 3.0 | 39.03 ± 3.2 | 38.92 ± 5.5 | 38.69 ± 2.3 | 38.25 ± 3.2 | 36.67 ± 3.0 | 36.71 ± 4.1 | 36.15 ± 2.7 | 33.19 ± 1.6 | 32.59 ± 0.8 |
5e | 13.98 ± 0.7 | 12.33 ± 0.4 | 9.97 ± 0.6 | 9.56 ± 0.4 | 9.22 ± 0.5 | 8.44 ± 0.4 | 8.10 ± 0.5 | 3.38 ± 0.2 | 2.59 ± 0.2 | 2.59 ± 0.2 | |
5j | 50.75 ± 0.0 | 46.22 ± 0.0 | 45.02 ± 0.0 | 44.01 ± 0.0 | 40.19 ± 0.1 | 39.56 ± 0.0 | 38.92 ± 0.1 | 37.72 ± 0.0 | 35.81 ± 0.0 | 34.46 ± 0.0 | |
8c | 77.98 ± 0.0 | 81.91 ± 0.1 | 84.35 ± 0.0 | 8.92 ± 0.0 | 1.69 ± 0.0 | 7.42 ± 0.0 | 4.99 ± 0.0 | 0.65 ± 0.0 | 14.32 ± 0.0 | 20.04 ± 0.0 | |
8d | 63.26 ± 0.3 | 83.54 ± 0.0 | 83.99 ± 0.0 | 22.09 ± 0.0 | 15.46 ± 0.0 | 13.21 ± 0.0 | 0.0 ± 0.0 | 12.37 ± 0.0 | 3.60 ± 0.0 | 6.75 ± 0.0 | |
8h | 81.13 ± 0.0 | 81.41 ± 0.1 | 81.97 ± 0.0 | 6.13 ± 0.0 | 0.0 ± 0.0 | 1.98 ± 0.0 | 1.86 ± 0.0 | 13.21 ± 0.0 | 7.82 ± 0.0 | 13.32 ± 0.0 | |
8i | 71.24 ± 0.2 | 83.86 ± 0.2 | 83.00 ± 0.0 | 61.65 ± 0.6 | 17.65 ± 0.0 | 9.71 ± 0.0 | 11.51 ± 0.0 | 15.25 ± 0.0 | 11.39 ± 0.0 | 14.61 ± 0.0 |
Candida albicans | Ergosterol Content (% ± SD) * | |||
---|---|---|---|---|
Comp. (µg/mL) | 5d | 6a | 7a | |
ATCC SC5314 | 16 | 73.8 ± 3.2 | 93.9 ± 4.3 | 95.5 ± 3.7 |
4 | 79.8 ± 3.2 | 57.3 ± 1.6 | 84.2 ± 3.8 | |
Clinical isolate | 16 | 74.3 ± 3.5 | 83.4 ± 4.1 | 99.9 ± 5.0 |
4 | 57.8 ± 2.7 | 66.1 ± 4.3 | 68.0 ± 2.0 |
Candida albicans | Comp. (µg/mL) | Ergosterol Conc. (% ± SD) | ||
---|---|---|---|---|
5d | 6a | 7a | ||
ATCC SC5314 | 16 | 114.4 ± 9.2 | 65.9 ± 5.3 | 72.7 ± 5.8 |
4 | 78.0 ± 6.2 | 67.9 ± 5.4 | 63.2 ± 3.8 | |
Clinical isolate | 16 | 51.7 ± 4.1 | 33.1 ± 2.6 | 112.4 ± 9.0 |
4 | 97.3 ± 7.8 | 52.6 ± 4.2 | 71.6 ± 5.7 |
Comp. | MIC (µg/mL) | Outcomes | |
---|---|---|---|
Alone | Combination | ||
5d AmB | 4 * 1.25 ** | 16 2.5 | No rules |
2 1.25 | Indifference | ||
2 2.5 | |||
1 2.5 | |||
0.5 2.25 | |||
0.25 2.5 |
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Staniszewska, M.; Kuryk, Ł.; Gryciuk, A.; Kawalec, J.; Rogalska, M.; Baran, J.; Łukowska-Chojnacka, E.; Kowalkowska, A. In Vitro Anti-Candida Activity and Action Mode of Benzoxazole Derivatives. Molecules 2021, 26, 5008. https://doi.org/10.3390/molecules26165008
Staniszewska M, Kuryk Ł, Gryciuk A, Kawalec J, Rogalska M, Baran J, Łukowska-Chojnacka E, Kowalkowska A. In Vitro Anti-Candida Activity and Action Mode of Benzoxazole Derivatives. Molecules. 2021; 26(16):5008. https://doi.org/10.3390/molecules26165008
Chicago/Turabian StyleStaniszewska, Monika, Łukasz Kuryk, Aleksander Gryciuk, Joanna Kawalec, Marta Rogalska, Joanna Baran, Edyta Łukowska-Chojnacka, and Anna Kowalkowska. 2021. "In Vitro Anti-Candida Activity and Action Mode of Benzoxazole Derivatives" Molecules 26, no. 16: 5008. https://doi.org/10.3390/molecules26165008