Prenylated Flavonoids with Potential Antimicrobial Activity: Synthesis, Biological Activity, and In Silico Study
Abstract
:1. Introduction
2. Results and Discussion
2.1. Synthesis
Structure Determination
2.2. In Vitro Antibacterial Effects on Human Pathogen Bacteria
Docking of 11 (S and R Enantiomers) and 8 with ATP-Binding Cassette (Multi-Drug ABC Transporter Sav1866 from S. aureus in Complex with AMP-PNP)
2.3. In Vitro Antifungal Effects on Human Pathogenic fungi
2.4. In Vitro Antibacterial Effects on Plant Pathogen bacteria
2.5. In Vitro 5-hLOX Enzyme Inhibition Assay
2.6. DPPH Radical Scavenging Activity
2.7. Cytotoxic Activity of 11 and 12
3. Materials and Methods
3.1. Chemistry
3.1.1. General Data
3.1.2. General Experimental Procedure for the Prenylation of Flavonoids
3.1.3. Physical Data of Prenylated Flavonoids
3.2. Biological Assays
3.2.1. In Vitro Antibacterial Activity Assays: Human Pathogens
Minimum Inhibitory Concentration Assay
Checkerboard Dilution Test
Time Kill Assay
Determination of Reactive Oxygen Species (ROS) Intrabacterial Levels
3.2.2. In Vitro Antifungal Activity Assays against Human Pathogens
Microorganisms and Media
Antifungal Susceptibility Testing
3.2.3. In Vitro Antibacterial Activity against Plant Pathogens
3.2.4. Statistics
3.3. In Vitro 5-LOX Enzyme Inhibition Assay
3.4. Docking of 11 (S and R Enantiomers) and with ABC Transporter
3.5. General Procedure to Determine the DPPH Radical Scavenging Activity
3.6. In Vitro Anticancer Activity of 11 and 12
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Acknowledgments
Conflicts of Interest
References
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Compound | MRSA 97-7 | MRSA 622-4 | ATCC 6538 |
---|---|---|---|
7 | 21% | 0% | 6% |
8 | 5% | 0% | 26% |
9 | 61% | 3% | 52% |
10 | 13% | 18% | 17% |
11 | 95% | 93% | 100% |
12 | 98% | 98% | 99% |
13 | 91% | 96% | 99% |
Compound | MRSA 97-7 | MRSA 622-4 | ATCC6538 |
---|---|---|---|
4 | >50 | >50 | >50 |
11 | 5 | 25 | 10 |
12 | 15 | 25 | 15 |
13 | 10 | 50 | 10 |
Vancomycin | 25 | 5 | 3.5 |
Ciprofloxacin | 100 | 10 | 2.5 |
Methicillin | 50 | 50 | 10 |
Agents | MIC Alone (µg/mL) | MIC Combined (µg/mL) | FICI | Outcome | Fold Reduction in Commercial Antibiotic MIC |
---|---|---|---|---|---|
11 Vancomycin | 5 25 | 0.5 2.5 | 0.2 | Synergy | 10 |
12 Vancomycin | 15 25 | 5 2.5 | 0.43 | Synergy | 10 |
13 Vancomycin | 10 25 | 0.5 2.5 | 0.15 | Synergy | 10 |
11 Ciprofloxacin | 5 100 | 2.5 10 | 0.6 | Partial Synergy | 10 |
12 Ciprofloxacin | 15 100 | 1 10 | 0.16 | Synergy | 10 |
11 Methicillin | 5 50 | 0.02 0.5 | 0.01 | Synergy | 100 |
Agents | MIC Alone (µg/mL) | MIC Combined (µg/mL) | FICI | Outcome | Fold Reduction in Commercial Antibiotic MIC |
---|---|---|---|---|---|
11 Ciprofloxacin | 25 10 | 2.5 0.1 | 0.1 | Synergy | 100 |
12 Ciprofloxacin | 25 10 | 5 0.1 | 0.2 | Synergy | 100 |
13 Ciprofloxacin | 50 10 | 5 0.1 | 0.1 | Synergy | 100 |
Strain | Agents | MIC Alone | MIC Combined | FICI | Outcome |
---|---|---|---|---|---|
MRSA 97-7 | 11 12 | 5 15 | 5 15 | 2 | Indifferent |
MRSA 622-4 | 11 12 | 25 25 | 2.5 25 | 1.1 | Indifferent |
Comp. | Candida albicans ATCC10231 | Cryptococcus neoformans ATCC32264 | Aspergillus flavus ATCC 9170 | Aspergillus fumigatus ATCC26934 | Aspergillus niger ATCC9029 | Microsporum gypseum CCC115, | Trichophyton rubrum CCC113 | Trichophyton mentagrophytes ATCC9972 |
---|---|---|---|---|---|---|---|---|
1 | >250 | >250 | >250 | >250 | >250 | >250 | >250 | >250 |
2 | >250 | >250 | >250 | >250 | >250 | >250 | >250 | >250 |
3 | >250 | >250 | >250 | >250 | >250 | >250 | >250 | >250 |
4 | >250 | >250 | >250 | >250 | >250 | >250 | >250 | >250 |
5 | >250 | >250 | >250 | >250 | >250 | >250 | >250 | >250 |
7 | >250 | >250 | >250 | >250 | >250 | >250 | >250 | >250 |
8 | >250 | >250 | >250 | >250 | >250 | >250 | >250 | >250 |
9 | 62.5/62.5 | 62.5/62.5 | >250 | >250 | >250 | 62.5/62.5 | 62.5/62.5 | 62.5/62.5 |
11 | >250 | 125/125 | >250 | >250 | >250 | 62.5/62.5 | 62.5/62.5 | 62.5/62.5 |
12 | 125/250 | 62.5/125 | >250 | >250 | >250 | 31.25/31.25 | 15.6/31.25 | 15.6/31.25 |
10 | >250 | 250/>250 | >250 | >250 | >250 | 250/250 | 250/250 | 250/250 |
13 | >250 | >250 | >250 | >250 | >250 | >250 | >250 | >250 |
Amph | 1.0/1.0 | 1.0/2.0 | 2.0/2.0 | 2.0/2.0 | 2.0/2.0 | - | - | - |
Terb | - | - | - | - | - | 0.008/0.015 | 0.004/0.008 | 0.004/0.015 |
Compound | C. neoformans Clinical Isolates | ||||
---|---|---|---|---|---|
IM983040 | IM972724 | IM042074 | IM983036 | IM00319 | |
9 | 125/250 | 125/250 | 125/125 | 125/125 | 125/125 |
11 | 250/>250 | 250/>250 | 250/>250 | 250/>250 | 250/>250 |
12 | 125/125 | 125/125 | 62.5/62.5 | 62.5/125 | 125/125 |
Amph | 0.25 | 0.25 | 0.12 | 0.25 | 0.5 |
Compound | C. albicans Clinical Strains | ||||
---|---|---|---|---|---|
C. albicans CCC 126 | C. albicans CCC 127 | C. albicans CCC 128 | C. albicans CCC 129 | C. albicans CCC 130 | |
9 | 62.5/62.5 | 62.5/62.5 | 62.5/62.5 | 62.5/62.5 | 62.5/62.5 |
12 | 125/125 | 125/125 | 125/125 | 125/125 | 125/125 |
Amph | 1.56 | 0.78 | 1.56 | 0.78 | 0.50 |
Compound | IC50/MIC (µM) | ||
---|---|---|---|
P. syringae | A. tumefaciens | P. carotovorum | |
1 | >31.3/>250 | >250/>250 | >250/>250 |
2 | >62.5/>250 | >250/>250 | >250/>250 |
3 | >250/>250 | >250/>250 | >250/>250 |
4 | >250/>250 | >250/>250 | >250/>250 |
5 | >250/>250 | >250/>250 | >250/>250 |
7 | <3.9/>250 | <3.9/>250 | <3.9/>250 |
8 | <3.9/>250 | <3.9/>250 | <3.9/>250 |
9 | <3.9/>250 | <3.9/>250 | <3.9/>250 |
11 | <3.9/>250 | <3.9/>250 | <3.9/>250 |
12 | <3.9/>250 | <3.9/>250 | <7.8/>250 |
10 | <15.6/>250 | <3.9/>250 | <3.9/>250 |
13 | <3.9/125 | <3.9/>250 | <3.9/125 |
Compound | % Inhibition |
---|---|
7 | 4 |
8 | 1 |
9 | 51 |
10 | 38 |
11 | 20 |
12 | 12 |
13 | 17 |
Compound | IC50 µM ± SD | Compound | IC50 µM ± SD |
---|---|---|---|
1 | NA | 7 | NA |
2 | 13.22 ± 0.49 | 8 | NA |
3 | 12.82 ± 0.48 | 9 | 9.49 ± 0.36 |
4 | NA | 10 | 10.32 ± 0.03 |
5 | NA | 11 | NA |
12 | NA | ||
Trolox | 22.54 ± 0.61 | 13 | NA |
Compound | IC50 (µM) ± SD | ||
---|---|---|---|
MDA-MB-231 | B16-F10 | MEF | |
11 | 53.94 ± 9.66 | 49.14 ± 3.38 | 48.45 ± 3.44 |
12 | 59.02 ± 3.25 | 45.53 ± 3.82 | 54.66 ± 3.35 |
Taxol | 0.21 ± 0.05 | 0.48 ± 0.08 | 0.40 ± 0.07 |
Etoposide | 1.33 ± 0.28 | 1.74 ± 0.32 | 1.03 ± 0.17 |
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Osorio, M.; Carvajal, M.; Vergara, A.; Butassi, E.; Zacchino, S.; Mascayano, C.; Montoya, M.; Mejías, S.; Martín, M.C.-S.; Vásquez-Martínez, Y. Prenylated Flavonoids with Potential Antimicrobial Activity: Synthesis, Biological Activity, and In Silico Study. Int. J. Mol. Sci. 2021, 22, 5472. https://doi.org/10.3390/ijms22115472
Osorio M, Carvajal M, Vergara A, Butassi E, Zacchino S, Mascayano C, Montoya M, Mejías S, Martín MC-S, Vásquez-Martínez Y. Prenylated Flavonoids with Potential Antimicrobial Activity: Synthesis, Biological Activity, and In Silico Study. International Journal of Molecular Sciences. 2021; 22(11):5472. https://doi.org/10.3390/ijms22115472
Chicago/Turabian StyleOsorio, Mauricio, Marcela Carvajal, Alejandra Vergara, Estefania Butassi, Susana Zacchino, Carolina Mascayano, Margarita Montoya, Sophia Mejías, Marcelo Cortez-San Martín, and Yesseny Vásquez-Martínez. 2021. "Prenylated Flavonoids with Potential Antimicrobial Activity: Synthesis, Biological Activity, and In Silico Study" International Journal of Molecular Sciences 22, no. 11: 5472. https://doi.org/10.3390/ijms22115472