Synthesis, Antimicrobial Activities, and Model of Action of Novel Tetralone Derivatives Containing Aminoguanidinium Moiety
Abstract
1. Introduction
2. Results and Discussion
2.1. Chemistry
2.2. Evaluation of In Vitro Antimicrobial Activity
2.3. 2D Exhibits Potent Anti-Biofilm Properties
2.4. 2D Destroys the Bacterial Structure
2.5. Fluorescence Microscopy
2.6. Membrane Permeabilization and Depolarization
2.7. Leakage of Protein and DNA
2.8. Docking Analysis
2.9. Hemolytic Activity and Cytotoxicity
2.10. In Vivo Efficacy
3. Materials and Methods
3.1. Chemistry
3.1.1. General
3.1.2. Synthesis of Intermediates
3.1.3. General Procedure for the Synthesis of Compounds 1A–1X and 2A–2J
3.2. Antibacterial Evaluation
3.2.1. MIC and MBC Testing
3.2.2. Growth Curve and Bactericidal Time-Kill Kinetics Assay
3.2.3. Biofilm Formation Inhibition and Elimination Assay
3.3. Mode of Action Study
3.3.1. Scanning Electron Microscopy (SEM) Analysis
3.3.2. Membrane Depolarization Assay
3.3.3. Fluorescence Microscopy Assay
3.3.4. Inner Membrane Permeabilization Assay
3.3.5. Bacterial DNA and Protein Leakage Experiment
3.3.6. Predicted Binding Mode of 2D in DHFR
3.4. Safety Assay
3.5. In Vivo Infection Model
3.6. Statistical Analysis
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
References
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Compounds | R | LogP | MW | Compounds | R | LogP | MW |
---|---|---|---|---|---|---|---|
1A | 2.560 | 326.15 | 1R | 3.018 | 386.07 | ||
1B | 2.542 | 326.15 | 1S | 2.987 | 386.07 | ||
1C | 2.341 | 326.15 | 1T | 3.513 | 360.12 | ||
1D | 2.561 | 344.14 | 1U | 3.351 | 360.12 | ||
1E | 2.599 | 344.14 | 1V | 1.168 | 333.16 | ||
1F | 2.542 | 344.14 | 1W | 3.394 | 384.20 | ||
1G | 2.400 | 344.14 | 1X | 3.776 | 350.21 | ||
1H | 2.419 | 344.14 | 2A | 2.494 | 274.18 | ||
1I | 3.59 | 376.15 | 2B | 2.845 | 288.20 | ||
1J | 3.654 | 376.15 | 2C | 3.123 | 302.21 | ||
1K | 4.097 | 444.14 | 2D | 3.360 | 316.23 | ||
1L | 3.03 | 342.12 | 2E | 3.654 | 330.24 | ||
1M | 3.036 | 342.12 | 2F | 3.972 | 344.26 | ||
1N | 2.82 | 342.12 | 2G | 4.295 | 358.27 | ||
1O | 3.825 | 376.09 | 2H | 4.608 | 372.29 | ||
1P | 3.859 | 376.09 | 2I | 3.008 | 286.18 | ||
1Q | 2.934 | 386.07 | 2J | 4.345 | 354.24 |
Compounds | Strains (MIC/MBC, µg/mL) | |||||
---|---|---|---|---|---|---|
E. faecium ATCC 35667 | S. aureus ATCC 29213 | K. pneumoniae ATCC 700603 | A. baumannii ATCC 19606 | P. aeruginosa ATCC 27853 | E. coli ATCC 25922 | |
1A | 4/16 | 4/16 | 16/16 | 8/16 | 32/>32 | 8/8 |
1B | 4/16 | 4/16 | 16/16 | 8/16 | 32/32 | 8/8 |
1C | 4/16 | 4/16 | 16/16 | 8/8 | 32/32 | 8/8 |
1D | 4/16 | 2/8 | 16/16 | 8/8 | 32/32 | 8/8 |
1E | 4/16 | 2/16 | 32/32 | 8/8 | >32/- | 8/8 |
1F | 8/16 | 4/16 | 32/32 | 16/16 | >32/- | 16/16 |
1G | 4/8 | 2/8 | 16/16 | 8/8 | 32/- | 8/16 |
1H | 4/16 | 2/8 | 16/32 | 8/8 | 32/32 | 4/16 |
1I | 4/8 | 2/16 | 32/32 | 8/8 | 32/32 | 4/4 |
1J | 2/4 | 2/16 | 16/32 | 8/8 | 16/>32 | 4/4 |
1K | 4/16 | 32/- | >32/- | >32/- | >32/- | >32/- |
1L | 4/8 | 2/8 | 16/32 | 4/4 | 32/>32 | 8/8 |
1M | 2/8 | 2/16 | 16/>32 | 4/16 | 16/32 | 8/8 |
1N | 2/8 | 2/4 | 16/32 | 4/16 | 16/32 | 4/8 |
1O | 2/16 | 4/8 | >32/- | 16/16 | >32/- | 8/16 |
1P | 2/8 | 2/8 | 32/32 | 8/16 | >32/- | 8/16 |
1Q | 2/8 | 4/8 | 32/32 | 8/8 | >32/- | 4/4 |
1R | 2/8 | 2/16 | 8/8 | 4/4 | >32/- | 8/8 |
1S | 4/8 | 2/8 | 16/16 | 8/16 | >32/- | 4/8 |
1T | 2/16 | 2/32 | >32/- | 16/32 | >32/- | 8/>32 |
1U | 2/16 | 2/4 | 8/32 | 4/16 | 16/>32 | 4/16 |
1V | 16/>32 | 8/32 | 32/- | 16/32 | >32/- | 16/32 |
1W | 2/16 | 2/16 | >32/- | 32/32 | >32/- | 32/32 |
1X | 2/4 | 2/4 | >32 | 4/8 | 32/>32 | 4/8 |
2A | 8/32 | 4/>32 | 16/>32 | 8/16 | 32/32 | 16/>32 |
2B | 4/16 | 1/8 | 8/8 | 8/8 | 16/32 | 4/8 |
2C | 2/8 | 1/8 | 8/8 | 4/4 | 8/16 | 4/4 |
2D | 2/4 | 0.5/4 | 16/32 | 4/16 | 16/32 | 4/8 |
2E | 2/4 | 2/2 | >32/- | 8/32 | 32/>32 | 4/16 |
2F | 2/4 | 2/8 | >32/- | >32/- | >32/- | >32/- |
2G | 2/8 | 2/8 | >32/- | >32/- | >32/- | >32/- |
2H | 4/8 | >32/- | >32/- | >32/- | >32/- | >32/- |
2I | 8/32 | 4/32 | 32/>32 | 16/32 | 32/32 | 16/32 |
2J | 2/8 | 4/8 | >32/- | 8/16 | 32/32 | 8/16 |
Levofloxacin | ≤1/2 | ≤1/≤1 | ≤1/4 | ≤1/2 | ≤1/2 | ≤1/≤1 |
Vancomycin | 2/16 | 1/4 | - | - | - | - |
Compounds | Strains (MIC/MBC, µg/mL) | |||||
---|---|---|---|---|---|---|
LMY45 | LMY46 | LMY47 | LMY48 | MRSA-1 | MRSA-2 | |
1A | 2/4 | 2/8 | 2/8 | 2/4 | 2/16 | 2/8 |
1B | 2/4 | 2/16 | 2/8 | 4/4 | 2/8 | 2/8 |
1C | 2/4 | 2/8 | 2/8 | 4/4 | 2/16 | 4/8 |
1D | 2/4 | 4/32 | 2/8 | 2/4 | 2/32 | 2/32 |
1E | 2/4 | 2/8 | 2/8 | 2/2 | 2/32 | 2/8 |
1F | 4/8 | 4/>32 | 4/8 | 4/16 | 4/32 | 4/16 |
1G | 2/4 | 2/8 | 2/8 | 2/2 | 2/16 | 2/16 |
1H | 2/4 | 2/>32 | 2/8 | 2/4 | 2/32 | 2/8 |
1I | 1/4 | 2/4 | 2/2 | 2/2 | 2/16 | 2/4 |
1J | 2/2 | 2/16 | 2/4 | 2/2 | 1/8 | 2/32 |
1K | 4/16 | 4/>32 | 4/8 | 4/8 | 16/- | 8/32 |
1L | 1/2 | 1/8 | 1/4 | 2/2 | 1/32 | 1/4 |
1M | 2/2 | 2/4 | 2/4 | 2/8 | 1/32 | 1/4 |
1N | 2/4 | 4/8 | 2/2 | 2/16 | 2/4 | 2/4 |
1O | 2/16 | 4/8 | ≤1/4 | ≤1/2 | 1/16 | 2/8 |
1P | 2/4 | 2/8 | 2/4 | ≤1/≤1 | 1/16 | 2/4 |
1Q | 2/4 | 2/4 | ≤1/4 | 2/2 | 1/8 | 2/8 |
1R | 2/4 | 2/4 | 2/8 | 2/16 | 2/16 | 2/4 |
1S | 2/4 | 1/4 | 2/4 | 4/8 | 1/4 | 1/4 |
1T | 1/4 | 1/4 | 1/4 | 4/4 | 1/8 | 2/8 |
1U | 2/2 | 1/4 | 2/4 | 4/8 | 2/32 | 1/4 |
1V | 4/8 | 4/32 | 8/32 | 8/8 | 8/16 | 8/8 |
1W | 2/8 | 2/8 | 2/8 | 2/4 | 4/32 | 2/4 |
1X | 2/4 | 2/2 | 2/8 | 2/8 | 4/8 | 1/4 |
2A | 2/4 | 2/4 | 2/2 | 1/2 | 2/2 | 1/2 |
2B | 8/16 | 8/16 | 4/8 | 2/2 | 32/32 | 4/4 |
2C | 8/32 | 8/16 | 2/8 | 4/32 | 4/16 | 2/4 |
2D | 2/2 | 4/32 | 1/4 | 2/2 | 1/16 | 1/4 |
2E | 1/4 | 1/4 | 2/4 | 1/2 | 1/8 | 1/2 |
2F | 2/4 | 2/4 | 2/8 | 1/2 | 2/2 | 1/2 |
2G | 4/16 | 4/8 | 2/2 | 2/4 | 4/16 | 4/4 |
2H | 4/8 | 2/16 | 2/16 | 4/4 | 4/16 | 4/16 |
2I | 2/4 | 2/2 | 2/8 | 1/2 | 2/16 | 1/2 |
2J | 4/16 | 2/>32 | 2/16 | 4/8 | 2/16 | 2/16 |
Vancomycin | 0.5/2 | 1/8 | 1/2 | 1/2 | 1/4 | 1/2 |
Compound | HC50 (µg/mL) | Cell Lines (IC50, µg/mL) | |||
---|---|---|---|---|---|
A549 | HepG2 | HEK 293-T | CaCo-2 | ||
2D | 50.65 | 3.57 | 6.00 | 13.09 | 9.86 |
SI | 101.30 | 7.14 | 12.00 | 26.18 | 19.72 |
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Zhang, Q.-J.; Li, Y.-X.; Ge, W.-B.; Bai, L.-X.; Xu, X.; Yang, Y.-J.; Liu, X.-W.; Li, J.-Y. Synthesis, Antimicrobial Activities, and Model of Action of Novel Tetralone Derivatives Containing Aminoguanidinium Moiety. Int. J. Mol. Sci. 2025, 26, 5980. https://doi.org/10.3390/ijms26135980
Zhang Q-J, Li Y-X, Ge W-B, Bai L-X, Xu X, Yang Y-J, Liu X-W, Li J-Y. Synthesis, Antimicrobial Activities, and Model of Action of Novel Tetralone Derivatives Containing Aminoguanidinium Moiety. International Journal of Molecular Sciences. 2025; 26(13):5980. https://doi.org/10.3390/ijms26135980
Chicago/Turabian StyleZhang, Qing-Jie, Yu-Xi Li, Wen-Bo Ge, Li-Xia Bai, Xiao Xu, Ya-Jun Yang, Xi-Wang Liu, and Jian-Yong Li. 2025. "Synthesis, Antimicrobial Activities, and Model of Action of Novel Tetralone Derivatives Containing Aminoguanidinium Moiety" International Journal of Molecular Sciences 26, no. 13: 5980. https://doi.org/10.3390/ijms26135980
APA StyleZhang, Q.-J., Li, Y.-X., Ge, W.-B., Bai, L.-X., Xu, X., Yang, Y.-J., Liu, X.-W., & Li, J.-Y. (2025). Synthesis, Antimicrobial Activities, and Model of Action of Novel Tetralone Derivatives Containing Aminoguanidinium Moiety. International Journal of Molecular Sciences, 26(13), 5980. https://doi.org/10.3390/ijms26135980