Synthesis and Biological Evaluation of Hydrazone Derivatives as Antifungal Agents
Abstract
:1. Introduction
2. Results and Discussion
2.1. Synthesis
R | R | R | ||||
---|---|---|---|---|---|---|
1ab | H | 6ab | 3,5-OH | 11a | 3,5-OMe | |
2ab | 3-OH | 7ab | 2,3,4-OH | 12a | 2,3,4-OMe | |
3ab | 4-OH | 8a | 3-OMe | 13a | 4-(2)pyridinyl) | |
4ab | 4-Cl | 9a | 4-OMe | 14a | 4-(4)NO2benzyl | |
5ab | 2,4-OH | 10a | 2,4-OMe | |||
1b | H | 6bc | 3,5-OH | 11b | 3,5-OMe | |
2b | 3-OH | 7b | 2,3,4-OH | 12b | 2,3,4-OMe | |
3b | 4-OH | 8b | 3-OMe | 13b | 4-(2)pyridinyl) | |
4b | 4-Cl | 9b | 4-OMe | 14bc | 4-(4)NO2benzyl | |
5b | 2,4-OH | 10b | 2,4-OMe | |||
1c | H | 10c | 2,4-OMe | 13c | 4-(2)pyridinyl) | |
8c | 3-Ome | 11c | 3,5-OMe | 11 | ||
9c | 4-Ome | 12c | 2,3,4-OMe | 12 |
2.2. Antifungal Activity
Column Heading | Aldehydes | Hydrazones | Hydrazines |
---|---|---|---|
C. glabrata | 2a, 5a, 7a, 13a, 14a | 7b, 12b | 12c |
C. parapsilosis | 2a, 6a, 7a, 8a, 10a, 11a, 13a | 2b, 5b, 6b, 7b, 11b, 13b | 10c, 13c |
C. tropicalis | 2a, 5a, 8a, 10a, 12a, 13a, 14a | 7b, 8b, 11b, 14b | 13c |
C. krusei | 2a, 5a, 12a, 13a, 14a | 7b, 9b, 12b | 8c |
C. lusitaneae | 2a, 4a, 6a, 13a, 14a | 2b, 6b, 7b, 9b, 11b | 13c |
C. albicans | 2a, 5a, 7a, 10a, 11a, 13a | 7b, 10b, 11b, 13b | 1c, 9c, 10c, 13c |
T. asahii | 1a, 2a, 5a, 6a, 8a, 13a | 3b, 5b, 6b, 7b, 11b, 13b | 9c, 10c, 12c, 13c |
Isolate | T. asahii | Isolate | C. parapsilosis | ||||
---|---|---|---|---|---|---|---|
13a | 7b | Fluc a | 13a | 7b | Fluc | ||
TAH 05 | 125 | 16 | Nt b | RL 01 | 32 | 16 | 64 |
TAH 06 | 64 | 16 | 32 | RL 05 | 32 | 16 | ≤1 |
TAH 07 | 64 | 16 | 8 | RL 07 | 32 | 16 | ≤1 |
TAH 09 | 250 | 8 | Nt b | RL 13 | 64 | 16 | ≤1 |
TAH 10 | 32 | 8 | 8 | RL 20 | 16 | 16 | 4 |
TAH 11 | 64 | 16 | 8 | RL 27 | 32 | 16 | ≤1 |
TAH 12 | 64 | 16 | Nt b | RL 32 | 32 | 16 | ≤1 |
TAH 13 | 64 | 16 | 4 | RL 33 | 32 | 16 | 2 |
TAH 14 | 32 | 16 | 4 | RL 36 | 32 | 8 | 2 |
TAH 15 | 32 | 16 | 4 | RL 38 | 32 | 8 | 4 |
2.3. Mechanism of Action
2.3.1. Evaluation of the Action on Cell Wall Stability: Sorbitol Protection Assay
Compounds | 2 Days | 7 Days | ||
---|---|---|---|---|
−/Sorbitol | +/Sorbitol | −/Sorbitol | +/Sorbitol | |
Anidulafungin | <1.0 | <1.0 | <1.0 | >125 |
7b | 16 | 16 | 16 | 16 |
13a | 32 | 32 | 32 | 32 |
2.3.2. Evaluation of the Action on Cell Membrane Stability: Cellular Leakage Assay
2.3.3. Evaluation of Action on Membrane Ergosterol: Ergosterol Effect Assay
2.4. Cell Viability and Genotoxicity
3. Experimental Section
3.1. General Information
3.2. Chemistry
3.2.1. General Procedure for the Preparation of Derivatives 8a–12a
3.2.2. General Procedure for the Preparation of Derivatives 13a–14a
3.2.3. General Procedure for the Preparation of Derivatives 1b–14b
3.2.4. General Procedure for the Preparation of Derivatives 1c, 8c–14c
3.3. Antifungal Activity
3.3.1. Isolates
3.3.2. Antifungal Activity Screening Assay
3.3.3. Minimal Inhibitory Concentration
3.4. Mechanisms of Action
3.4.1. Sorbitol Protection Assay
3.4.2. Cellular Leakage Assay
3.4.3. Ergosterol Effect Assay
3.5. Cytotoxicity
3.5.1. Cell Viability
3.5.2. Genotoxicity
3.6. Statistical Analysis
4. Conclusions
Acknowledgments
Author Contributions
Conflicts of Interest
References
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Casanova, B.B.; Muniz, M.N.; De Oliveira, T.; De Oliveira, L.F.; Machado, M.M.; Fuentefria, A.M.; Gosmann, G.; Gnoatto, S.C.B. Synthesis and Biological Evaluation of Hydrazone Derivatives as Antifungal Agents. Molecules 2015, 20, 9229-9241. https://doi.org/10.3390/molecules20059229
Casanova BB, Muniz MN, De Oliveira T, De Oliveira LF, Machado MM, Fuentefria AM, Gosmann G, Gnoatto SCB. Synthesis and Biological Evaluation of Hydrazone Derivatives as Antifungal Agents. Molecules. 2015; 20(5):9229-9241. https://doi.org/10.3390/molecules20059229
Chicago/Turabian StyleCasanova, Bruna B., Mauro N. Muniz, Thayse De Oliveira, Luís Flavio De Oliveira, Michel M. Machado, Alexandre M. Fuentefria, Grace Gosmann, and Simone C. B. Gnoatto. 2015. "Synthesis and Biological Evaluation of Hydrazone Derivatives as Antifungal Agents" Molecules 20, no. 5: 9229-9241. https://doi.org/10.3390/molecules20059229