Synthesis, Characterization, and Biological Evaluation of Tetrahydropyrimidines: Dual-Activity and Mechanism of Action
Abstract
:1. Introduction
2. Materials and Methods
2.1. Chemistry
Experimental Procedure for Synthesis of 4a–k
2.2. Sample Preparation for MS Analysis
3. Results and Discussion
3.1. Chemistry
3.2. X-ray Crystallography
3.3. Biology
3.3.1. Antimicrobial Activity
3.3.2. Cytotoxic Activity of the Compounds
3.3.3. Effects of the Compounds 4b and 4k on Cell Cycle
3.3.4. Morphological Evaluation of HeLa Cell Death Mode Induced by the Compounds 4b and 4k
3.3.5. Inhibitory Effects of Compounds on α-Glucosidase Enzymatic Activity
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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Bond Lengths [Å] | |||
---|---|---|---|
O1—C20 | 1.203 (3) | N1—C1 | 1.339 (2) |
O2—C20 | 1.334 (3) | N1—C4 | 1.453 (2) |
O2—C21 | 1.442 (2) | N2—C1 | 1.373 (3) |
O3—C7 | 1.354 (2) | N2—C2 | 1.410 (3) |
O3—C22 | 1.424 (3) | N2—C18 | 1.472 (3) |
O4—C11 | 1.354 (2) | C3—C2 | 1.336 (3) |
O4—C8 | 1.402 (2) | C4—C3 | 1.517 (2) |
O5—C11 | 1.196 (3) | S1—C1 | 1.6733 (19) |
O6—C24 | 1.423 (3) | O6—C23 | 1.425 (3) |
Bond angles [°] | |||
C11—O4—C8 | 116.71 (15) | C1—N1—C4 | 122.60 (14) |
C24—O6—C23 | 110.08 (16) | N1—C1—N2 | 115.90 (16) |
C20—O2—C21 | 116.98 (17) | N1—C1—S1 | 120.25 (14) |
Torsion angles [°] | |||
C4—N1—C1—N2 | −23.7 (2) | C2—C3—C20—O1 | −19.9 (3) |
N1—C4—C3—C2 | −31.1 (2) | C4—C3—C20—O1 | 157.6 (2) |
C2—N2—C1—N1 | −10.4 (2) | C2—C3—C20—O2 | 162.28 (16) |
N1—C4—C3—C20 | 151.29 (15) | C4—C3—C20—O2 | −20.2 (2) |
C18—N2—C1—S1 | −8.3 (3) | O3—C7—C8—O4 | −3.0 (3) |
C2—N2—C1—S1 | 20.2 (3) | C11—O4—C8—C9 | −80.8 (3) |
C1—N2—C2—C3 | 169.09 (13) | C11—O4—C8—C7 | 103.7 (2) |
C5—C4—C3—C2 | 92.44 (18) | C17—C12—C11—O5 | 9.3 (3) |
D—H•••A | D—H | H•••A | D•••A | D—H•••A |
---|---|---|---|---|
N1—H1•••O6 | 0.86 | 2.23 | 2.897 (2) | 134.9 |
C19—H19B•••O1 | 0.93 | 2.95 | 3.809 (2) | 154.0 |
C9—H9•••S1 1 | 0.96 | 2.61 | 3.363 (3) | 135.7 |
C21—H21C•••O5 2 | 0.96 | 2.61 | 3.363 (3) | 135.7 |
C22—H22C•••O6 3 | 0.96 | 2.62 | 3.407 (3) | 139.5 |
Tested Compounds | Staphylococcus aureus | Bacillus subtilis | Klebsiella oxytoca | Proteus mirabilis | Escherichia coli |
---|---|---|---|---|---|
MIC (mg/mL) | |||||
4a | 1.62 | 3.25 | 1.62 | 0.81 | 1.62 |
4b | 1.62 | 3.25 | 1.62 | 0.81 | 1.62 |
4c | 1.62 | 3.25 | 1.62 | 1.62 | 1.62 |
4d | 0.81 | 3.25 | 1.62 | 0.81 | 1.62 |
4e | 3.25 | 3.25 | 3.25 | ND | 1.62 |
4f | 3.25 | 3.25 | 3.25 | 1.62 | 3.25 |
4g | 3.25 | 3.25 | 1.62 | 0.81 | 1.62 |
4h | 3.25 | 3.25 | 3.25 | 3.25 | 3.25 |
4i | 3.25 | 3.25 | 1.62 | 1.62 | 1.62 |
4j | 3.25 | 3.25 | 3.25 | 1.62 | 3.25 |
4k | 3.25 | 3.25 | 3.25 | 3.25 | 3.25 |
Streptomycin | 0.031 | 0.016 | 0.008 | 0.062 | 0.062 |
Tested Compounds | Trichophyton mentagrophytes | Mucor mucedo | Penicillium italicum | Aspergillus flavus | Aspergillus niger |
---|---|---|---|---|---|
MIC (mg/mL) | |||||
4a | 0.40 | 1.62 | 1.62 | 1.62 | 1.62 |
4b | 0.40 | 1.62 | 1.62 | 1.62 | 0.81 |
4c | 0.40 | 1.62 | 1.62 | 0.40 | 0.81 |
4d | 0.40 | 1.62 | 1.62 | 1.62 | 1.62 |
4e | 0.20 | 1.62 | 1.62 | 1.62 | 1.62 |
4f | 0.20 | 1.62 | 1.62 | 1.62 | 0.81 |
4g | 0.40 | 1.62 | 1.62 | 1.62 | 1.62 |
4h | 0.81 | 1.62 | 1.62 | 1.62 | 1.62 |
4i | 0.81 | 1.62 | 1.62 | 1.62 | 1.62 |
4j | 0.40 | 1.62 | 1.62 | 1.62 | 1.62 |
4k | 0.20 | 1.62 | 1.62 | 0.81 | 1.62 |
Fluconazole | 0.25 | 1 | 1 | 1 | 0.5 |
Tested Compounds | HeLa | K562 | MDA-MB-231 | MRC-5 |
---|---|---|---|---|
IC50 [µM] Average ± SD | ||||
4a | 97.40 ± 5.40 | 78.98 ± 7.49 | 144.50 ± 8.29 | 186.92 ± 4.66 |
4b | 52.59 ± 4.45 | 76.83 ± 5.01 | 115.65 ± 8.71 | 111.87 ± 10.85 |
4c | >200 | 180.21 ± 9.15 | >200 | 195.83 ± 5.89 |
4d | >200 | 164.66 ± 8.50 | >200 | 192.71 ± 10.32 |
4e | 197.22 ± 3.93 | 149.08 ± 5.74 | >200 | 127.98 ± 3.20 |
4f | 135.34 ± 9.32 | 122.91 ± 8.52 | 161.29 ± 9.69 | 196.08 ± 5.54 |
4g | 197.49 ± 3.55 | 152.68 ± 2.58 | >200 | 193.22 ± 9.59 |
4h | 120.85 ± 9.96 | 79.94 ± 6.73 | 114.02 ± 12.86 | 77.82 ± 2.57 |
4i | 169.06 ± 4.12 | 99.36 ± 9.38 | >200 | 152.34 ± 10.15 |
4j | 78.11 ± 5.78 | 67.97 ± 6.53 | 122.61 ± 2.19 | 104.17 ± 8.61 |
4k | 43.63 ± 1.49 | 39.11 ± 2.90 | 74.12 ± 1.25 | 87.23 ± 7.31 |
cisPt | 4.91 ± 0.74 | 6.89 ± 0.21 | 14.74 ± 0.36 | 9.35 ± 1.29 |
Compounds | IC50 [µM] |
---|---|
4a | 312.91 ± 7.73 |
4b | 291.77 ± 6.67 |
4c | ND |
4d | 1121.91 ± 20.59 |
4e | 674.81 ± 5.65 |
4f | 767.91 ± 5.91 |
4g | 191.80 ± 5.95 |
4h | 932.75 ± 25.16 |
4i | 418.02 ± 5.68 |
4j | ND |
4k | 1083.41 ± 54.54 |
acarbose | 304.21 ± 14.62 |
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Milović, E.; Janković, N.; Petronijević, J.; Joksimović, N.; Kosanić, M.; Stanojković, T.; Matić, I.; Grozdanić, N.; Klisurić, O.; Stefanović, S. Synthesis, Characterization, and Biological Evaluation of Tetrahydropyrimidines: Dual-Activity and Mechanism of Action. Pharmaceutics 2022, 14, 2254. https://doi.org/10.3390/pharmaceutics14102254
Milović E, Janković N, Petronijević J, Joksimović N, Kosanić M, Stanojković T, Matić I, Grozdanić N, Klisurić O, Stefanović S. Synthesis, Characterization, and Biological Evaluation of Tetrahydropyrimidines: Dual-Activity and Mechanism of Action. Pharmaceutics. 2022; 14(10):2254. https://doi.org/10.3390/pharmaceutics14102254
Chicago/Turabian StyleMilović, Emilija, Nenad Janković, Jelena Petronijević, Nenad Joksimović, Marijana Kosanić, Tatjana Stanojković, Ivana Matić, Nađa Grozdanić, Olivera Klisurić, and Srđan Stefanović. 2022. "Synthesis, Characterization, and Biological Evaluation of Tetrahydropyrimidines: Dual-Activity and Mechanism of Action" Pharmaceutics 14, no. 10: 2254. https://doi.org/10.3390/pharmaceutics14102254
APA StyleMilović, E., Janković, N., Petronijević, J., Joksimović, N., Kosanić, M., Stanojković, T., Matić, I., Grozdanić, N., Klisurić, O., & Stefanović, S. (2022). Synthesis, Characterization, and Biological Evaluation of Tetrahydropyrimidines: Dual-Activity and Mechanism of Action. Pharmaceutics, 14(10), 2254. https://doi.org/10.3390/pharmaceutics14102254