Derivatives of Trimethoxybenzoic Acid and Gallic Acid as Potential Efflux Pump Inhibitors: In Silico and In Vitro Studies
Abstract
1. Introduction
2. Results and Discussion
2.1. Chemistry
2.2. Molecular Docking
2.3. Antibacterial Activity and Antibiotic Potentiation
2.4. Efflux Pump Inhibition
2.5. Inhibition of Biofilm Formation and Quorum-Sensing Assays
2.6. Antifungal Activity
2.7. In Silico ADME Properties
3. Materials and Methods
3.1. Chemistry
3.1.1. General Procedure for the Synthesis of Compounds 3–13
3,4,5-Trimethoxy-N-(2-(4-methylpiperazin-1-yl)ethyl)benzamide (13)
3.2. Molecular Docking
3.3. Culture Media and Chemicals
3.4. Microorganisms
3.5. Antibacterial and Antibiotic Potentiation Assays
3.6. Efflux Pump Inhibition
3.7. Inhibition of Biofilm Formation
3.8. Quorum-Sensing Inhibition
3.9. Antifungal Assays
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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Compound | Docking Score | ||||
---|---|---|---|---|---|
AcrB | AcrA | TolC | NorA | ||
HH | LD | ||||
1 | −5.9 | −5.1 | −4.5 | −5.5 | −4.1 |
2 | −5.6 | −4.3 | −3.7 | −5.5 | −4.0 |
3 | −6.5 | −4.9 | −4.3 | −6.0 | −4.5 |
4 | −6.2 | −5.5 | −4.6 | −5.9 | −4.2 |
5 | −7.3 | −5.7 | −4.7 | −6.4 | −7.3 |
6 | −7.6 | −6.4 | −5.4 | −6.7 | −6.2 |
7 | −6.8 | −5.0 | −6.0 | −5.7 | −4.4 |
8 | −6.7 | −5.0 | −5.8 | −5.9 | −4.7 |
9 | −8.9 | −5.8 | −6.7 | −6.5 | −5.9 |
10 | −9.8 | −6.5 | −7.1 | −7.3 | −6.2 |
11 | −6.6 | −4.7 | −5.3 | −5.7 | −3.9 |
12 | −7.0 | −5.0 | −5.0 | −5.9 | −4.8 |
13 | −7.1 | −5.0 | −5.6 | −5.9 | −4.8 |
Reserpine | −8.1 | 5.6 | 4.6 | −7.5 | −4.1 |
Compound | RFI ± SD | |
---|---|---|
S. aureus 272123 | S. Typhimurium SL1344 | |
3 | ND | ND |
4 | ND | ND |
5 | 0.08 ± 0.07 | 0.22 ± 0.02 |
6 | 0.30 ± 0.05 | 0.22 ± 0.11 |
7 | −0.02 ± 0.01 | −0.07 ± 0.03 |
8 | −0.07 ± 0.03 | −0.07 ± 0.05 |
9 | −0.35 ± 0.01 | −0.41 ± 0.01 |
10 | −0.21 ± 0.03 | −0.36 ± 0.01 |
11 | −0.03 ± 0.03 | −0.06 ± 0.01 |
12 | 0.17 ± 0.03 | −0.01 ± 0.01 |
13 | 0.14 ± 0.02 | 0.06 ± 0.01 |
Reserpine | 0.30 ± 0.12 | 0.04 ± 0.07 |
CCCP | ND | 0.16 ± 0.06 |
Compound | Molecular Weight | # Rotatable Bonds | # H-Bond Acceptors | # H-Bond Donors | ilogP |
---|---|---|---|---|---|
Reserpine | 608.68 | 10 | 10 | 1 | 5.16 |
5 | 330.38 | 9 | 4 | 2 | 3.12 |
6 | 355.39 | 8 | 5 | 2 | 2.46 |
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Neves, A.R.; Durães, F.; Freitas-Silva, J.; Szemerédi, N.; Martins-da-Costa, P.; Pinto, E.; Correia-da-Silva, M.; Spengler, G.; Sousa, E. Derivatives of Trimethoxybenzoic Acid and Gallic Acid as Potential Efflux Pump Inhibitors: In Silico and In Vitro Studies. Int. J. Mol. Sci. 2022, 23, 14468. https://doi.org/10.3390/ijms232214468
Neves AR, Durães F, Freitas-Silva J, Szemerédi N, Martins-da-Costa P, Pinto E, Correia-da-Silva M, Spengler G, Sousa E. Derivatives of Trimethoxybenzoic Acid and Gallic Acid as Potential Efflux Pump Inhibitors: In Silico and In Vitro Studies. International Journal of Molecular Sciences. 2022; 23(22):14468. https://doi.org/10.3390/ijms232214468
Chicago/Turabian StyleNeves, Ana Rita, Fernando Durães, Joana Freitas-Silva, Nikoletta Szemerédi, Paulo Martins-da-Costa, Eugénia Pinto, Marta Correia-da-Silva, Gabriella Spengler, and Emília Sousa. 2022. "Derivatives of Trimethoxybenzoic Acid and Gallic Acid as Potential Efflux Pump Inhibitors: In Silico and In Vitro Studies" International Journal of Molecular Sciences 23, no. 22: 14468. https://doi.org/10.3390/ijms232214468
APA StyleNeves, A. R., Durães, F., Freitas-Silva, J., Szemerédi, N., Martins-da-Costa, P., Pinto, E., Correia-da-Silva, M., Spengler, G., & Sousa, E. (2022). Derivatives of Trimethoxybenzoic Acid and Gallic Acid as Potential Efflux Pump Inhibitors: In Silico and In Vitro Studies. International Journal of Molecular Sciences, 23(22), 14468. https://doi.org/10.3390/ijms232214468