Trifluoromethylcinnamanilide Michael Acceptors for Treatment of Resistant Bacterial Infections
Abstract
:1. Introduction
2. Results and Discussion
2.1. Synthesis and Physicochemical Properties
2.2. In Vitro Antimicrobial Activity
2.3. In Vitro Cell Viability
2.4. Structure–Activity Relationships
2.5. Docking Study
3. Materials and Methods
3.1. General Methods
3.2. Synthesis
General Procedure for Synthesis of Carboxamide Derivatives 1a–2q
3.3. Lipophilicity Determination by HPLC
3.4. In Vitro Antibacterial Evaluation
3.5. Determination of Minimum Bactericidal Concentrations
3.6. MTT Assay
3.7. In Vitro Antimycobacterial Evaluation
3.8. In Vitro Cell Viability Analysis
3.9. Docking Study
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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No. | R1 | R2 | R3 | log k | log D6.5 | log D7.4 | log P 1 | log P 2 | Clog P 2 | σPh-R3 1 |
---|---|---|---|---|---|---|---|---|---|---|
1a | CF3 | H | H | 0.5234 | 0.4663 | 0.4633 | 3.93 | 4.10 | 4.5470 | 0.60 |
1b | CF3 | H | 2-F | 0.5375 | 0.4804 | 0.4805 | 3.84 | 4.26 | 4.3476 | 1.02 |
1c | CF3 | H | 3-F | 0.6333 | 0.5768 | 0.5775 | 4.19 | 4.26 | 4.9476 | 0.82 |
1d | CF3 | H | 4-F | 0.5760 | 0.5178 | 0.5175 | 3.77 | 4.26 | 4.9476 | 0.62 |
1e | CF3 | H | 2-Cl | 0.6568 | 0.6010 | 0.6012 | 4.56 | 4.66 | 4.6676 | 1.02 |
1f | CF3 | H | 3-Cl | 0.8016 | 0.7477 | 0.7468 | 4.80 | 4.66 | 5.5176 | 0.85 |
1g | CF3 | H | 4-Cl | 0.7982 | 0.7431 | 0.7413 | 4.67 | 4.66 | 5.5176 | 0.75 |
1h | CF3 | H | 2-CF3 | 0.5710 | 0.5135 | 0.5119 | 4.43 | 5.02 | 4.4308 | 0.91 |
1i | CF3 | H | 3-CF3 | 0.8807 | 0.8249 | 0.8287 | 5.29 | 5.02 | 5.8808 | 0.89 |
1j | CF3 | H | 4-CF3 | 0.9247 | 0.8706 | 0.8666 | 4.60 | 5.02 | 5.8808 | 0.95 |
1k | CF3 | H | 2,4-F | 0.5906 | 0.5318 | 0.5326 | 3.99 | 4.42 | 4.5808 | 1.04 |
1l | CF3 | H | 3,5-F | 0.8186 | 0.7657 | 0.7636 | 4.52 | 4.42 | 5.1808 | 1.12 |
1m | CF3 | H | 2,4-Cl | 0.9782 | 0.9284 | 0.9279 | 5.41 | 5.22 | 5.4708 | 1.12 |
1n | CF3 | H | 2,5-Cl | 0.9612 | 0.9096 | 0.9091 | 5.69 | 5.22 | 5.4708 | 1.22 |
1o | CF3 | H | 3,5-Cl | 1.2028 | 1.1506 | 1.1488 | 5.68 | 5.22 | 6.3208 | 1.11 |
1p | CF3 | H | 3,5-CF3 | 1.3648 | 1.3126 | 1.3121 | 6.75 | 5.94 | 6.9216 | 1.05 |
2a | H | CF3 | H | 0.5351 | 0.4751 | 0.4684 | 3.96 | 4.10 | 4.5470 | 0.60 |
2b | H | CF3 | 2-F | 0.5515 | 0.4924 | 0.4811 | 3.87 | 4.26 | 4.3476 | 1.02 |
2c | H | CF3 | 3-F | 0.6462 | 0.5877 | 0.5750 | 4.23 | 4.26 | 4.9476 | 0.82 |
2d | H | CF3 | 4-F | 0.5887 | 0.5283 | 0.5159 | 3.79 | 4.26 | 4.9476 | 0.62 |
2e | H | CF3 | 2-Cl | 0.6614 | 0.6050 | 0.5917 | 4.60 | 4.66 | 4.6676 | 1.02 |
2f | H | CF3 | 3-Cl | 0.8095 | 0.7526 | 0.7402 | 4.82 | 4.66 | 5.5176 | 0.85 |
2g | H | CF3 | 4-Cl | 0.8054 | 0.7483 | 0.7351 | 4.70 | 4.66 | 5.5176 | 0.75 |
2h | H | CF3 | 2-CF3 | 0.5798 | 0.5187 | 0.5081 | 4.46 | 5.02 | 4.4308 | 0.91 |
2i | H | CF3 | 3-CF3 | 0.8867 | 0.8300 | 0.8177 | 5.33 | 5.02 | 5.8808 | 0.89 |
2j | H | CF3 | 4-CF3 | 0.9319 | 0.8743 | 0.8617 | 4.63 | 5.02 | 5.8808 | 0.95 |
2k | H | CF3 | 2,4-F | 0.6011 | 0.5396 | 0.5225 | 4.01 | 4.42 | 4.5808 | 1.04 |
2l | H | CF3 | 3,5-F | 0.8253 | 0.7678 | 0.7516 | 4.55 | 4.42 | 5.1808 | 1.12 |
2m | H | CF3 | 2,4-Cl | 0.9735 | 0.9196 | 0.9033 | 5.44 | 5.22 | 5.4708 | 1.12 |
2n | H | CF3 | 2,5-Cl | 0.9583 | 0.9037 | 0.8903 | 5.72 | 5.22 | 5.4708 | 1.22 |
2o | H | CF3 | 3,5-Cl | 1.2024 | 1.1511 | 1.1440 | 5.72 | 5.22 | 6.3208 | 1.11 |
2p | H | CF3 | 3,5-CF3 | 1.3665 | 1.3169 | 1.3098 | 6.80 | 5.94 | 6.9216 | 1.05 |
No. | MIC [µM] MBC [µM] | IC50 [µM] THP-1 24 h | |||||||||
---|---|---|---|---|---|---|---|---|---|---|---|
SA | MRSA1 | MRSA2 | MRSA3 | EF | VRE1 | VRE2 | VRE3 | MM | MS | ||
1c | 12.9 25.9 | 25.9 25.9 | 12.9 12.9 | 12.9 12.9 | n.a. – | n.a. – | n.a. – | n.a. – | n.a. – | 51.7 – | >30 |
1f | 12.3 12.3 | 6.14 6.14 | 6.14 6.14 | 6.14 12.3 | n.a. – | n.a. – | n.a. – | n.a. – | n.a. – | 24.6 – | >10 |
1g | 24.6 49.1 | 12.3 24.6 | 6.14 6.14 | 12.3 24.6 | n.a. – | n.a. – | n.a. – | n.a. – | n.a. – | 24.6 – | >10 |
1i | 11.1 22.3 | 11.1 11.1 | 2.78 2.78 | 2.78 22.3 | n.a. – | n.a. – | n.a. – | n.a. – | n.a. – | 11.1 – | >10 |
1j | 2.78 2.78 | 2.78 2.78 | 1.39 1.39 | 2.78 5.57 | 22.3 22.3 | 22.3 22.3 | 44.5 44.5 | 22.3 22.3 | 0.348 – | 11.1 – | >30 |
1o | 0.694 0.694 | 1.39 2.78 | 0.694 0.694 | 0.694 1.39 | 11.1 22.2 | 22.2 22.2 | 22.2 22.2 | 22.2 22.2 | 22.2 – | 11.1 – | >30 |
1p | 1.17 1.17 | 2.34 2.34 | 1.17 1.17 | 0.585 1.17 | n.a. – | n.a. – | n.a. – | n.a. – | 2.34 – | 9.36 – | 6.7 ± 1.1 |
2i | 1.39 1.39 | 2.78 2.78 | 1.39 1.39 | 2.78 2.78 | 11.1 11.1 | 11.1 22.3 | 11.1 44.5 | 11.1 11.1 | 2.78 – | n.a. – | >10 |
2p | 0.146 0.146 | 0.585 0.585 | 0.293 0.585 | 0.293 0.293 | 2.34 4.68 | 2.34 4.68 | 4.68 9.36 | 2.34 2.34 | 0.293 – | 1.17 – | 8.9 ± 1.3 |
AMP | 5.72 >5.72 | 45.8 >45.8 | 45.8 >45.8 | 45.8 >45.8 | 2.81 2.81 | 11.5 11.5 | 11.5 11.5 | 11.5 11.5 | – | – | – |
INH | – | – | – | – | – | – | – | – | 36.6 – | 117 – | – |
No. | Conc. | S. aureus Respiration Inhibition (%) |
---|---|---|
1c | 2× MIC (1× MBC) | 97.9 |
1f | 1× MIC (1× MBC) | 96.0 |
1g | 4× MIC (2× MBC) | 71.1 |
1i | 1× MIC (0.5× MBC) | 98.0 |
1j | 0.5× MIC (0.5× MBC) | 97.9 |
1o | 0.25× MIC (0.25× MBC) | 97.8 |
1p | 1× MIC (1× MBC) | 97.7 |
2i | 1× MIC (1× MBC) | 98.1 |
2p | 2× MIC (2× MBC) | 98.0 |
AMP | 8× MIC (>8× MBC) | 90.0 |
CPX | 32× MIC (32× MBC) | 92.8 |
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Strharsky, T.; Pindjakova, D.; Kos, J.; Vrablova, L.; Smak, P.; Michnova, H.; Gonec, T.; Hosek, J.; Oravec, M.; Jendrzejewska, I.; et al. Trifluoromethylcinnamanilide Michael Acceptors for Treatment of Resistant Bacterial Infections. Int. J. Mol. Sci. 2022, 23, 15090. https://doi.org/10.3390/ijms232315090
Strharsky T, Pindjakova D, Kos J, Vrablova L, Smak P, Michnova H, Gonec T, Hosek J, Oravec M, Jendrzejewska I, et al. Trifluoromethylcinnamanilide Michael Acceptors for Treatment of Resistant Bacterial Infections. International Journal of Molecular Sciences. 2022; 23(23):15090. https://doi.org/10.3390/ijms232315090
Chicago/Turabian StyleStrharsky, Tomas, Dominika Pindjakova, Jiri Kos, Lucia Vrablova, Pavel Smak, Hana Michnova, Tomas Gonec, Jan Hosek, Michal Oravec, Izabela Jendrzejewska, and et al. 2022. "Trifluoromethylcinnamanilide Michael Acceptors for Treatment of Resistant Bacterial Infections" International Journal of Molecular Sciences 23, no. 23: 15090. https://doi.org/10.3390/ijms232315090