Novel Thiazolylketenyl Quinazolinones as Potential Anti-MRSA Agents and Allosteric Modulator for PBP2a
Abstract
:1. Introduction
2. Results and Discussion
2.1. Chemistry
2.2. Antibacterial Activity
2.3. Hemolytic Assay
2.4. Resistance Study
2.5. ADMET Study
2.6. Antibiofilm Activity
2.7. Metabolic Activity
2.8. Membrane Damage Assay
2.8.1. Membrane Depolarization Assay
2.8.2. Study of Inner Membrane Permeabilization
2.9. The Leakage of Intracellular Protein
2.10. Intracellular ROS Accumulation
2.11. Interaction between Compound 4 and DNA
2.11.1. DNA Binding Study
2.11.2. Competitive Binding Study
2.12. Allosteric Modulation of Compound 4 with PBP2a
2.12.1. Contents of PBP2a and Drug Combination
2.12.2. Allosteric Site Binding Affinity of PBP2a
2.12.3. Molecular Docking
2.13. Summary of Anti-MRSA Behavior of Thiazolylketenyl Quinazolinones
3. Materials and Methods
3.1. Instruments and Chemicals
3.2. Synthesis of Intermediates and Thiazolylketenyl Quinazolinones and Analogs
3.2.1. Synthesis of Intermediates 2–3 and 15–16
3.2.2. Synthesis of Intermediate 14
3.2.3. Synthesis of (E)-2-(3-(thiazol-2-yl)acryloyl)quinazolin-4(3H)-one (4)
3.2.4. Synthesis of (E)-2-(3-(thiazol-5-yl)acryloyl)quinazolin-4(3H)-one (5a)
3.2.5. Synthesis of (E)-2-(3-(2-phenylthiazol-5-yl)acryloyl)quinazolin-4(3H)-one (5b)
3.2.6. Synthesis of (E)-2-(3-(furan-2-yl)acryloyl)quinazolin-4(3H)-one (6a)
3.2.7. Synthesis of (E)-2-(3-(5-methylfuran-2-yl)acryloyl)quinazolin-4(3H)-one (6b)
3.2.8. Synthesis of (E)-2-(3-(5-(hydroxymethyl)furan-2-yl)acryloyl)quinazolin-4(3H)-one (6c)
3.2.9. Synthesis of (E)-2-(3-(thiophen-2-yl)acryloyl)quinazolin-4(3H)-one (7a)
3.2.10. Synthesis of (E)-2-(3-(3-methylthiophen-2-yl)acryloyl)quinazolin-4(3H)-one (7b)
3.2.11. Synthesis of (E)-2-(3-(benzofuran-3-yl)acryloyl)quinazolin-4(3H)-one (8a)
3.2.12. Synthesis of (E)-2-(3-(benzo[b]thiophen-3-yl)acryloyl)quinazolin-4(3H)-one (8b)
3.2.13. Synthesis of (E)-2-(3-(1H-indol-3-yl)acryloyl)quinazolin-4(3H)-one (8c)
3.2.14. Synthesis of (E)-7-fluoro-2-(3-(thiazol-2-yl)acryloyl)quinazolin-4(3H)-one (17a)
3.2.15. Synthesis of (E)-7-chloro-2-(3-(thiazol-2-yl)acryloyl)quinazolin-4(3H)-one (17b)
3.2.16. Synthesis of (E)-6,8-dichloro-2-(3-(thiazol-2-yl)acryloyl)quinazolin-4(3H)-one (17c)
3.2.17. Synthesis of (E)-6-methyl-2-(3-(thiazol-2-yl)acryloyl)quinazolin-4(3H)-one (17d)
3.2.18. Synthesis of (E)-8-methyl-2-(3-(thiazol-2-yl)acryloyl)quinazolin-4(3H)-one (17e)
3.3. Biological Assay
3.3.1. Antibacterial Activity
3.3.2. Hemolytic Assay
3.3.3. Resistance Study
3.3.4. ADMET Study
3.3.5. Inhibition of Biofilm
3.3.6. Metabolic Activity
3.3.7. Membrane Depolarization Assay
3.3.8. Inner Membrane Permeability
3.3.9. Leakage of Cellular Protein
3.3.10. Reactive Oxygen Species (ROS) Production
3.3.11. Interactions of Compound 4 with Calf Thymus DNA
3.3.12. Measurement of PBP2a Contents
3.3.13. Drug Combination
3.3.14. Determination of Allosteric Site Binding Affinity by Fluorescent Quenching
3.3.15. Molecular Docking
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Sample Availability
References
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Number | Solvent | Base | Temperature (°C) | Time (h) | Yields (%) |
---|---|---|---|---|---|
1 | CH3CN | K2CO3 | 80 | 8 | - |
2 | CH3CN | Cs2CO3 | 80 | 8 | - |
3 | DMF | K2CO3 | 80 | 8 | - |
4 | DMF | K2CO3 | 120 | 8 | - |
5 | DMF | Cs2CO3 | 80 | 8 | - |
6 | DMF | NaH | 25 | 8 | - |
7 | DMF | NaH | 80 | 8 | - |
Compds. | Gram-Positive Bacteria a | Gram-Negative Bacteria b | |||||||||
---|---|---|---|---|---|---|---|---|---|---|---|
MRSA | S. a. | S. a. 25923 | S. a. 29213 | E. f. | K. p. | E. c. | E. c. 25922 | P. a. | P. a. 27853 | A. b. | |
4 | 0.5 | 4 | 8 | 1 | 2 | 2 | 2 | 0.5 | 4 | 2 | 64 |
5a | 16 | 32 | 16 | 1 | 32 | 16 | 32 | 8 | 16 | 8 | 2 |
5b | 64 | 64 | 128 | 32 | 128 | 256 | 128 | 32 | 128 | 128 | 256 |
6a | 4 | 16 | 16 | 32 | 16 | 2 | 4 | 32 | 8 | 64 | 16 |
6b | 8 | 8 | 8 | 16 | 16 | 16 | 8 | 64 | 16 | 128 | 16 |
6c | 128 | 32 | 64 | 8 | 128 | 128 | 128 | 64 | 8 | 128 | 32 |
7a | 8 | 32 | 64 | 128 | 256 | 64 | 4 | 32 | 16 | 16 | 2 |
7b | 8 | 8 | 4 | 16 | 4 | 8 | 4 | 8 | 8 | 0.5 | 4 |
8a | 16 | 32 | 8 | 8 | 32 | 2 | 32 | 16 | 4 | 64 | 4 |
8b | 8 | 4 | 8 | 16 | 32 | 2 | 16 | 16 | 32 | 32 | 1 |
8c | 64 | 8 | 4 | 8 | 16 | 128 | 32 | 32 | 64 | 16 | 32 |
17a | 32 | 32 | 16 | 32 | 4 | 8 | 64 | 4 | 4 | 32 | 16 |
17b | 128 | 8 | 16 | 8 | 8 | 4 | 32 | 4 | 4 | 2 | 8 |
17c | 4 | 16 | 8 | 32 | 1 | 16 | 8 | 8 | 2 | 2 | 2 |
17d | 8 | 16 | 32 | 64 | 2 | 4 | 16 | 64 | 2 | 4 | 4 |
17e | 8 | 32 | 16 | 32 | 1 | 16 | 32 | 8 | 4 | 32 | 4 |
Norfloxacin | 4 | 8 | 4 | 1 | 2 | 4 | 4 | 2 | 4 | 1 | 2 |
Properties | 4 | Norfloxacin |
---|---|---|
Molecular weight (g/mol) (<500) | 283.31 | 319.33 |
MLOGP (≤4.15) | 0.84 | 1.04 |
H-bond acceptors (<10) | 4 | 5 |
H-bond donors (<5) | 1 | 2 |
rotatable bonds (<10) | 3 | 3 |
Lipinski’s Rule | Yes | Yes |
Bioavailability score | 0.55 | 0.55 |
GI absorption | High | High |
BBB permean | No | No |
Compounds | PBP2a Contents in Treated MRSA (pg/mL) | MIC (Alone or Combination) |
---|---|---|
Control | 405.94 ± 21.19 | – |
Compound 4 | 345.16 ± 2.80 | 0.5 (alone) |
Cefdinir | 189.00 ± 11.04 | 1 (alone) |
Compound 4 + Cefdinir | 127.47 ± 14.94 | 0.125/0.125 (combination) |
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© 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
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Dai, J.; Battini, N.; Zang, Z.; Luo, Y.; Zhou, C. Novel Thiazolylketenyl Quinazolinones as Potential Anti-MRSA Agents and Allosteric Modulator for PBP2a. Molecules 2023, 28, 4240. https://doi.org/10.3390/molecules28104240
Dai J, Battini N, Zang Z, Luo Y, Zhou C. Novel Thiazolylketenyl Quinazolinones as Potential Anti-MRSA Agents and Allosteric Modulator for PBP2a. Molecules. 2023; 28(10):4240. https://doi.org/10.3390/molecules28104240
Chicago/Turabian StyleDai, Jie, Narsaiah Battini, Zhonglin Zang, Yan Luo, and Chenghe Zhou. 2023. "Novel Thiazolylketenyl Quinazolinones as Potential Anti-MRSA Agents and Allosteric Modulator for PBP2a" Molecules 28, no. 10: 4240. https://doi.org/10.3390/molecules28104240