Evaluation of 1,2-Benzothiazine 1,1-Dioxide Derivatives In Vitro Activity towards Clinical-Relevant Microorganisms and Fibroblasts
Abstract
:1. Introduction
2. Results
2.1. Chemistry
2.2. Biological Tests
3. Discussion
4. Materials and Methods
4.1. Chemistry
4.2. General Procedure for the Preparation of Series 6 and Series 7 Compounds
Synthesis of Series 7 Compounds (7a–7l):
4.3. Biological Tests
- (a)
- the five following bacterial strains and one fungal strain from the American Tissue and Cell Culture Collection (ATCC) were applied in this study: Staphylococcus aureus 6538; Pseudomonas aeruginosa 15442, Enterococcus faecalis 29212, Klebsiella pneumoniae 70063, Escherichia coli 2592, Candida albicans 10231.
- (b)
- fibroblasts L929 (ATCC® CCL-1) were used to evaluate cytotoxic potential of the tested compounds.
- (c)
- all microbial strains and fibroblast line are part of Strain and Line Collection of Pharmaceutical Microbiology and Parasitology Department of Medical University of Wroclaw
- (d)
- 1,2-benzothiazine 1,1-dioxide derivatives were synthesized in the Department of Chemistry of Drugs of Medical University of Wroclaw. All tested compounds were divided to three series. Series 6 includes seven compounds, series 7 includes 12 compounds and series 3 is represented by one compound. All tested compounds are presented in the Figure 6, Table 7 and Table 8 below.
4.3.1. Evaluation of the Antimicrobial Activity of 1,2-Benzothiazine 1,1-Dioxide Derivatives Using Disc Diffusion Method
4.3.2. Evaluation of the Minimum Inhibitory Concentration (MIC) of 1,2-Benzothiazine 1,1-Dioxide Derivatives vs. Povidone-Iodine (PVP-I) and Polihexanidine (PHMB) Antiseptics Using Serial Microdilution Method
4.3.3. Cytotoxicity Assay on L929 Fibroblast Cells
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Conflicts of Interest
References
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Sample Availability: Samples of the compounds are not available from the authors. |
X-ray | DFT | |
---|---|---|
S1—O1 | 1.420 (3) | 1.468 |
S1—O2 | 1.420 (4) | 1.467 |
S1—N1 | 1.618 (4) | 1.684 |
S1—C1 | 1.742 (6) | 1.790 |
C7—O3 | 1.275 (6) | 1.254 |
C8—N1 | 1.429 (6) | 1.433 |
C9—O4 | 1.297 (5) | 1.331 |
N1—C16 | 1.477 (6) | 1.462 |
C17—O5 | 1.219 (6) | 1.229 |
C17—N2 | 1.318 (6) | 1.368 |
N3—C22 | 1.427 (6) | 1.420 |
O2—S1—O1 | 119.3 (2) | 120.18 |
N1—S1—C1 | 102.4 (3) | 101.34 |
C5—C6—C7—C8 | −170.0 (6) | −169.97 |
C8—C9—C10—C15 | −30.0 (8) | −39.05 |
C8—N1—C16—C17 | −69.0 (5) | −62.23 |
S1—N1—C16—C17 | 85.8 (5) | 92.72 |
N1—C16—C17—N2 | 178.1 (4) | 178.14 |
C19—N3—C22—C23 | 7.3 (5) | 10.27 |
7i | 7a | |
---|---|---|
C1—S1—N1—C16 | −106.8 (4) | −107.7 (4) |
S1—N1—C16—C17 | 85.7 (4) | 82.7 (4) |
N1—C16—C17—O5 | 4.0 (6) | 0.3 (7) |
N1—C16—C17—N2 | 178.1 (4) | −178.9 (5) |
C16—C17—N2—C18 | −1.4 (7) | −7.1 (7) |
C17—N2—C18—c19 | 129.8 (5) | 139.7 (7) |
N2—C18—C19—N3 | 58.5 (6) | 57.7 (6) |
C18—C19—N3—C22 | 166.5 (5) | 165.0 (5) |
C19—N3—C22—C23 | 7.3 (7) | 15.5 (7) |
N3—C22—C23—C24 | −174.9 (5) | −176.6 (5) |
D-H···A | D-H | H···A | D···A | D-H···A | |
---|---|---|---|---|---|
O4-H4A···O3 | 0.82 | 1.69 | 2.433 (6) | 150 | (in crystal) |
O4-H4A···O3 | 1.011 | 1.599 | 2.519 | 148.90 | (DFT) |
Zones of S. aureus Growth Inhibition [mm] | ||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
4 mg | 2 mg | 1 mg | 0.5 mg | 0.25 mg | 0.2 mg | 0.125 mg | 0.1 mg | 0.0625 mg | 0.05 mg | 0.0312 mg | 0.025 mg | |
6d | 0 | 0 | 8 (±0) | 8 (±0) | 8 (±0) | N/A | 9 (±0) | N/A | 9 (±0) | N/A | 10 (±0) | N/A |
6g | N/A | N/A | N/A | N/A | N/A | 6 (±0) | N/A | 6 (±0) | N/A | 8 (±0) | N/A | 9 (±0) |
7a | 0 | 0 | 9.33 (±0.58) | 9.66 (±1.15) | 8.33 (±0.58) | N/A | 9 (±1) | N/A | 0 | N/A | N/A | N/A |
7b | 10 (±0) | 10 (±0) | 10.33 (±0.58) | 10 (±0) | 9.33 (±0.58) | N/A | 7.33 (±1.15) | N/A | 0 | N/A | N/A | N/A |
7e | 0 | 0 | 0 | 9 (±0) | 9 (±0) | N/A | 8 (±0) | N/A | 6 (±0) | N/A | N/A | N/A |
7f | 0 | 0 | 0 | 9 (±0) | 8 (±0) | N/A | 9 (±0) | N/A | 10 (±0) | N/A | 10 (±0) | N/A |
7h | 0 | 10 (±0) | 8 (±0) | 9 (±0) | 9 (±0) | N/A | 0 | N/A | 0 | N/A | N/A | N/A |
7l | 0 | 0 | 9 (±0) | 9 (±0) | 8 (±0) | N/A | 9 (±0) | N/A | 0 | N/A | N/A | N/A |
Zones of E. faecalis Growth Inhibition [mm] | ||||||||||||
6d | 0 | 0 | 0 | 10 (±0) | 10 (±0) | N/A | 11 (±0) | N/A | 10 (±0) | N/A | 10.33 (±0.58) | N/A |
7b | 0 | 0 | 0 | 9 (±0) | 8 (±0) | N/A | 8 (±0) | N/A | 0 | N/A | N/A | N/A |
7d | 0 | 0 | 0 | 8 (±0) | 7 (±0) | N/A | 7 (±0) | N/A | N/A | N/A | N/A | N/A |
7f | 0 | 0 | 0 | 6 (±0) | 8 (±0) | N/A | 10 (±0) | N/A | 11 (±0) | N/A | 11.33 (±0.58) | N/A |
7g | 0 | 0 | 0 | 0 | 9 (±0) | N/A | 10 (±0) | N/A | 8 (±0) | N/A | N/A | N/A |
7j | 0 | 0 | 0 | 9 (±0) | 9 (±0) | N/A | 9 (±0) | N/A | 6 (±0) | N/A | N/A | N/A |
MIC [mg/mL] | |||||
---|---|---|---|---|---|
S. aureus | E. faecalis | P. aeruginosa | E. coli | K. pneumoniae | |
3e | 1.04 | 2.08 | 1.04 | 1.04 | 1.04 |
Series 6 | |||||
6a | 0.078 | 0.078 | 2.5 | 1.25 | 1.25 |
6b | 0.024 | 0.024 | 3.125 | 3.125 | 3.125 |
6c | 0.065 | 0.065 | 2.07 | 2.07 | 2.07 |
6d | 0.024 | 0.024 | 3.125 | 3.125 | 3.125 |
6e | 0.024 | 0.024 | 3.125 | 3.125 | 3.125 |
6f | 0.195 | 0.195 | 3.125 | 3.125 | 3.125 |
6g | 0.00975 | 0.00975 | 1.25 | 1.25 | 1.25 |
Series 7 | |||||
7a | 0.26 | 0.065 | 4.16 | 4.16 | 4.16 |
7b | 0.195 | 0.39 | 6.25 | 6.25 | 6.25 |
7c | 0.13 | 0.13 | 2.07 | 2.07 | 2.07 |
7d | 0.024 | 0.024 | 3.125 | 3.125 | 3.125 |
7e | 0.0655 | 0.0655 | 0.525 | 0.525 | 0.525 |
7f | 0.024 | 0.024 | 3.125 | 3.125 | 3.125 |
7g | 0.024 | 0.024 | 3.125 | 3.125 | 3.125 |
7h | 0.78 | 0.78 | 3.125 | 3.125 | 3.125 |
7i | 0.78 | 0.78 | 1.56 | 1.56 | 1.56 |
7j | 0.195 | 0.39 | 3.125 | 3.125 | 3.125 |
7k | 0.156 | 0.156 | 0.625 | 0.625 | 0.625 |
7l | 0.195 | 0.39 | 1.56 | 3.125 | 3.125 |
Antiseptics | |||||
PHMB | 0.024 | 0.097 | 3.125 | 0.097 | 0.39 |
PVP-I | 1.56 | 6.25 | 12.5 | 6.25 | 3.125 |
MIC [mg/mL] | Cytotoxicity [%] | |
---|---|---|
3e | 1.04 *,** 2.08 # | 59.55 (±12.39) 66.32 (±5.44) |
Series 6 | ||
6a | 0.078 *,# | −1.51 (±5.30) |
6b | 0.024 *,# | 15.11 (±1.19) |
6c | 0.065 *,# | 15.61 (±7.80) |
6d | 0.024 *,# | 79.76 (±0.62) |
6e | 0.024 *,# | 23.61 (±5.21) |
6f | 0.195 *,# | 15.10 (±2.69) |
6g | 0.00975 *,# | 21.25 (±6.26) |
Series 7 | ||
7a | 0.26 * 0.065 # | 2.40 (±14.82) 20.97 (±6.99) |
7b | 0.195 * 0.39 # | −10.83 (±5.19) −3.795 (±6.94) |
7c | 0.13 *,# | −2.32 (1.43) |
7d | 0.024 *,# | −11.09 (±1.96) |
7e | 0.0655 *,# | 2.68 (±4.20) |
7f | 0.024 *,# | 2.92 (±13.42) |
7g | 0.024 *,# | 9.68 (±4.09) |
7h | 0.78 *,# | 38.26 (±10.86) |
7i | 0.78 *,# 1.56 ** | 65.60 (±1.55) 61.64 (±4.98) |
7j | 0.195 * 0.39 # | 4.30 (±6.19) 32.53 (±0.67) |
7k | 0.156 *,# | 17.27 (±13.97) |
7l | 0.195 * 0.39 # | 5.90 (±3.49) 3.11 (±2.30) |
Series 6 | ||
---|---|---|
Compound | R1 | R2 |
6a | H | o-OCH3 |
6b | Cl | o-F |
6c | F | o-OCH3 |
6d | F | m-CF3 |
6e | F | - |
6f | OCH3 | - |
6g | OCH3 | m-CF3 |
Series 7 | |||
---|---|---|---|
Compound | R1 | R3 | X |
7a | H | - | CH |
7b | H | - | N |
7c | H | o-OCH3 | CH |
7d | H | o-F | CH |
7e | Br | - | N |
7f | Cl | o-F | CH |
7g | F | o-F | CH |
7h | F | m-CF3 | CH |
7i | F | - | CH |
7j | OCH3 | - | CH |
7k | OCH3 | - | N |
7l | OCH3 | o-OCH3 | CH |
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Dudek-Wicher, R.K.; Szczęśniak-Sięga, B.M.; Wiglusz, R.J.; Janczak, J.; Bartoszewicz, M.; Junka, A.F. Evaluation of 1,2-Benzothiazine 1,1-Dioxide Derivatives In Vitro Activity towards Clinical-Relevant Microorganisms and Fibroblasts. Molecules 2020, 25, 3503. https://doi.org/10.3390/molecules25153503
Dudek-Wicher RK, Szczęśniak-Sięga BM, Wiglusz RJ, Janczak J, Bartoszewicz M, Junka AF. Evaluation of 1,2-Benzothiazine 1,1-Dioxide Derivatives In Vitro Activity towards Clinical-Relevant Microorganisms and Fibroblasts. Molecules. 2020; 25(15):3503. https://doi.org/10.3390/molecules25153503
Chicago/Turabian StyleDudek-Wicher, Ruth K., Berenika M. Szczęśniak-Sięga, Rafał J. Wiglusz, Jan Janczak, Marzenna Bartoszewicz, and Adam F. Junka. 2020. "Evaluation of 1,2-Benzothiazine 1,1-Dioxide Derivatives In Vitro Activity towards Clinical-Relevant Microorganisms and Fibroblasts" Molecules 25, no. 15: 3503. https://doi.org/10.3390/molecules25153503