New 2-Phenylthiazoles as Potential Sortase A Inhibitors: Synthesis, Biological Evaluation and Molecular Docking
Abstract
:1. Introduction
2. Results and Discussion
2.1. Chemistry
2.2. Biological Assays
2.2.1. Antimicrobial Activity—Initial In Vitro Qualitative Screening Study
2.2.2. Antimicrobial Activity—In Vitro Quantitative Assay
2.2.3. Anti-Biofilm Activity Assay
2.3. Molecular Docking
2.3.1. Sequence Alignment and Validation of the Generated Model for E. faecalis ATCC 29212 Sortase A
2.3.2. Binding Mode of the C1–8 2-Phenylthiazoles to the Catalytic Site of Sortases
3. Materials and Methods
3.1. General Information
3.2. Chemistry
3.3. Biological Assays
3.3.1. Antimicrobial Activity—Initial In Vitro Qualitative Screening Study
3.3.2. Antimicrobial Activity—In Vitro Quantitative Assay
3.3.3. Anti-Biofilm Activity Assay
3.4. Molecular Docking Study
4. Conclusions
Acknowledgments
Author Contributions
Conflicts of Interest
References
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Sample Availability: Samples of all the compounds are available from the authors. |
Compound | Enterococcus faecalis ATCC 29212 | Staphylococcus aureus ATCC 6538 | Staphylococcus aureus BAA 1026 | Staphylococcus saprophyticus ATCC 15305 | Bacillus subtilis ATCC 6633 | Escherichia coli ATCC 8739 | Pseudomonas aeruginosa ATCC 27853 |
---|---|---|---|---|---|---|---|
C1 | 14 | 9 | 10 | 10 | 0 | 0 | 0 |
C2 | 13 | 8 | 8 | 11 | 0 | 0 | 0 |
C3 | 14 | 8 | 7 | 13 | 0 | 0 | 0 |
C4 | 12 | 8 | 8 | 10 | 0 | 0 | 0 |
C5 | 13 | 9 | 8 | 12 | 0 | 0 | 0 |
C6 | 14 | 10 | 0 | 0 | 0 | 0 | 0 |
C7 | 10 | 0 | 0 | 0 | 0 | 0 | 0 |
C8 | 12 | 9 | 10 | 10 | 0 | 0 | 0 |
Ciprofloxacin | 15 | 14 | 15 | 16 | 14 | 14 | 16 |
DMSO | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
Compound | Enterococcus faecalis ATCC 29212 | Staphylococcus aureus ATCC 6538 | Staphylococcus aureus BAA 1026 | Staphylococcus saprophyticus ATCC 15305 |
---|---|---|---|---|
C1 | 0.25 | >1 | >1 | >1 |
C2 | 0.125 | >1 | 0.125 | 0.032 |
C3 | 0.062 | >1 | >1 | 0.032 |
C4 | 0.062 | >1 | 0.032 | 0.125 |
C5 | 0.062 | >1 | >1 | 0.016 |
C6 | 0.016 | >1 | - | - |
C7 | 0.25 | - | - | - |
C8 | 0.032 | >1 | >1 | 0.002 |
Ciprofloxacin | 0.002 | 0.0005 | 0.001 | 0.0005 |
Compound | Enterococcus faecalis ATCC 29212 | Staphylococcus aureus ATCC 6538 | Staphylococcus aureus BAA 1026 | Staphylococcus saprophyticus ATCC 15305 | Bacillus subtilis ATCC 6633 | Escherichia coli ATCC 8739 | Pseudomonas aeruginosa ATCC 27853 |
---|---|---|---|---|---|---|---|
C1 | 0.004 | 1 | 1 | >1 | 1 | 1 | 1 |
C2 | 0.002 | 1 | 1 | >1 | 1 | 1 | 1 |
C3 | 0.002 | >1 | >1 | >1 | 1 | >1 | 1 |
C4 | 0.004 | >1 | 0.062 | >1 | 1 | >1 | 1 |
C5 | 0.002 | 1 | 0.25 | >1 | 1 | 1 | >1 |
C6 | 0.004 | 1 | 0.25 | >1 | >1 | 1 | >1 |
C7 | 0.008 | 1 | 0.25 | >1 | >1 | 1 | 1 |
C8 | 0.016 | >1 | >1 | >1 | >1 | 1 | 1 |
Compound | E. faecalis Sortase A | S. aureus Sortase A | ||
---|---|---|---|---|
Binding Energy (kcal/mol) | Inhibition Constant (nM) | Binding Energy (kcal/mol) | Inhibition Constant (nM) | |
C1 | −9.54 | 101.64 | −8.16 | 1043.84 |
C2 | −9.46 | 116.34 | −7.25 | 4849.25 |
C3 | −10.54 | 18.80 | −9.00 | 252.88 |
C4 | −9.94 | 51.75 | −7.28 | 4609.83 |
C5 | −10.64 | 15.88 | −8.50 | 588.05 |
C6 | −10.56 | 18.17 | −7.90 | 1618.89 |
C7 | −9.67 | 81.62 | −8.37 | 732.32 |
C8 | −10.01 | 45.98 | −8.61 | 488.41 |
Compound | Ligand Atom ID | Interacting AA Residue | Bond Length (Å) |
---|---|---|---|
C1 | N1 | Thr122-OH | 2.9 |
N1 | Thr122-C=O | 3.1 | |
C2 | N1 | Thr122-OH | 3.1 |
C3 | N1 | Thr122-OH | 2.8 |
N2 | Ser85-C=O | 3.0 | |
O-nitro | Arg224-C=NH | 2.8 | |
O-nitro | Arg224-C-NH2 | 3.5 | |
O-nitro | Asn221-C-NH2 | 2.5 | |
C4 | N1 | Thr122-OH | 2.9 |
N2 | Ser85-C=O | 2.9 | |
O-methoxy | Arg224-C=NH | 3.0 | |
O-methoxy | Arg224-C-NH2 | 3.3 | |
C5 | N1 | Thr122-OH | 2.8 |
N-cyano | Asn221-C=O | 3.5 | |
C6 | N1 | Thr122-OH | 2.9 |
N1 | Thr122-C=O | 3.1 | |
C7 | N2 | Thr122-OH | 2.9 |
N2 | Thr122-C=O | 3.1 | |
OH | Glu135-COOH | 2.8 | |
NH2 | Asp82-COOH | 3.0 | |
C8 | N1 | Thr122-OH | 2.9 |
N1 | Thr122-OH | 3.0 |
Parameter | E. faecalis | S. aureus |
---|---|---|
Volume | 580.03 Ǻ3 | 387.65 Ǻ3 |
Internal surface | 1022.95 Ǻ2 | 654.68 Ǻ2 |
H bond donor AA | 23 | 9 |
H bond acceptor AA | 56 | 24 |
Non polar AA | 29% | 52% |
Polar non-ionic AA | 34% | 14% |
Cationic AA | 21% | 24% |
Anionic AA | 16% | 10% |
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Oniga, S.D.; Araniciu, C.; Palage, M.D.; Popa, M.; Chifiriuc, M.-C.; Marc, G.; Pirnau, A.; Stoica, C.I.; Lagoudis, I.; Dragoumis, T.; et al. New 2-Phenylthiazoles as Potential Sortase A Inhibitors: Synthesis, Biological Evaluation and Molecular Docking. Molecules 2017, 22, 1827. https://doi.org/10.3390/molecules22111827
Oniga SD, Araniciu C, Palage MD, Popa M, Chifiriuc M-C, Marc G, Pirnau A, Stoica CI, Lagoudis I, Dragoumis T, et al. New 2-Phenylthiazoles as Potential Sortase A Inhibitors: Synthesis, Biological Evaluation and Molecular Docking. Molecules. 2017; 22(11):1827. https://doi.org/10.3390/molecules22111827
Chicago/Turabian StyleOniga, Smaranda Dafina, Cătălin Araniciu, Mariana Doina Palage, Marcela Popa, Mariana-Carmen Chifiriuc, Gabriel Marc, Adrian Pirnau, Cristina Ioana Stoica, Ioannis Lagoudis, Theodoros Dragoumis, and et al. 2017. "New 2-Phenylthiazoles as Potential Sortase A Inhibitors: Synthesis, Biological Evaluation and Molecular Docking" Molecules 22, no. 11: 1827. https://doi.org/10.3390/molecules22111827
APA StyleOniga, S. D., Araniciu, C., Palage, M. D., Popa, M., Chifiriuc, M. -C., Marc, G., Pirnau, A., Stoica, C. I., Lagoudis, I., Dragoumis, T., & Oniga, O. (2017). New 2-Phenylthiazoles as Potential Sortase A Inhibitors: Synthesis, Biological Evaluation and Molecular Docking. Molecules, 22(11), 1827. https://doi.org/10.3390/molecules22111827