Interactions of N-Mannich Bases of Pyrrolo[3,4-c]pyrrole with Artificial Models of Cell Membranes and Plasma Proteins, Evaluation of Anti-Inflammatory and Antioxidant Activity
Abstract
:1. Introduction
2. Materials and Methods
2.1. Biological Evaluation
2.1.1. Cell Line and Culture Conditions
2.1.2. Tested Compounds
2.1.3. Lipoxygenase Inhibition Assay
2.1.4. Experimental Design
- Protective properties against ROS or NO (RNS) formation
- Scavenging exogenous ROS or NO (RNS)
2.1.5. DCF-DA Assay
2.1.6. Griess Assay
2.1.7. MDA Assay
2.1.8. FHA Assay
2.1.9. Statistical Analysis
2.2. Interactions with Artificial Models of Cell Membranes
2.2.1. Chemicals
2.2.2. Differential Scanning Calorimetry (DSC)
2.3. Molecular Docking Studies
2.4. Spectroscopic Studies
2.4.1. Fluorescence Quenching
2.4.2. Circular Dichroism Spectroscopy
2.4.3. FT-IR Measurements
2.5. Computational Investigations
2.6. Chemistry
3. Results
3.1. 15-Lipoxygenase (15-LOX) Inhibition Studies
3.1.1. In Vitro 15-LOX Inhibition Assay
3.1.2. Molecular Docking Study
3.2. Interactions with Artificial Models of Cell Membranes
3.3. Antioxidant Activity within Cells
3.4. Human Serum Albumin (HSA) and Alpha-1-Acid Glycoprotein (AAG) Ligand-Binding Assay
3.4.1. Fluorescence Quenching, Binding Constants, Site Markers and Thermodynamic Studies
3.4.2. Circular Dichroism Spectra
3.4.3. Fourier-Transform Infrared Spectroscopic Measurements
3.4.4. Site Markers and Molecular Docking Studies
3.5. In Silico ADME, Physicochemical and Drug-Likeness Predictions
4. Discussion
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Compound | IC50 [µM] |
---|---|
7a | 12.63 (0.06) * |
7b | 10.95 (0.04) * |
7c | 12.47 (0.06) * |
7l | 12.81 (0.03) * |
7m | 12.73 (0.05) * |
7n | 14.07 (0.04) * |
zileuton | 13.41 (0.04) |
15-LOX | |
---|---|
7a | −9.7 |
7b | −8.6 |
7c | −9.0 |
7l | −8.5 |
7m | −7.3 |
7n | −8.8 |
Compound | Tm (°C) | T1/2 |
---|---|---|
7a | 22.65 +/− 0.17 | 1.10 +/− 0.12 |
7b | 21.90 +/− 0.18 | 1.63 +/− 0.10 |
7c | 22.40 +/− 0.08 | 1.20 +/− 0.12 |
7l | 21.73 +/− 0.38 | 1.55 +/− 0.29 |
7m | 22.75 +/− 0.13 | 0.98 +/− 0.05 |
7n | 22.38 +/− 0.15 | 1.13 +/− 0.15 |
Compound | Concentration [μM] | 24 h Incubation with Compounds [E/E0] | 1 h Incubation with Compounds [E/E0] | ||||
---|---|---|---|---|---|---|---|
With | With | ||||||
H2O2 | H2O2 | ||||||
Mean | SEM | p | Mean | SEM | p | ||
H2O2 (incubated only 1 h) | 100 | 1.675 | 0.021 | * | 1.798 | 0.033 | * |
7a | 100 | 0.566 | 0.006 | * | 0.845 | 0.021 | * |
50 | 0.575 | 0.008 | * | 0.853 | 0.014 | * | |
10 | 0.669 | 0.003 | * | 0.888 | 0.012 | * | |
7b | 100 | 0.606 | 0.004 | * | 0.949 | 0.006 | * |
50 | 0.614 | 0.007 | * | 1.010 | 0.008 | ||
10 | 0.619 | 0.006 | * | 1.121 | 0.009 | * | |
7c | 100 | 0.544 | 0.003 | * | 0.939 | 0.004 | * |
50 | 0.551 | 0.002 | * | 1.091 | 0.004 | ||
10 | 0.575 | 0.005 | * | 1.226 | 0.034 | * | |
7l | 100 | 0.573 | 0.006 | * | 0.851 | 0.011 | * |
50 | 0.561 | 0.004 | * | 0.949 | 0.004 | * | |
10 | 0.544 | 0.008 | * | 1.029 | 0.003 | ||
7m | 100 | 0.567 | 0.009 | * | 1.286 | 0.087 | * |
50 | 0.557 | 0.011 | * | 1.244 | 0.023 | * | |
10 | 0.547 | 0.005 | * | 1.112 | 0.067 | * | |
7n | 100 | 0.631 | 0.009 | * | 1.418 | 0.055 | * |
50 | 0.515 | 0.006 | * | 1.418 | 0.023 | * | |
10 | 0.528 | 0.004 | * | 1.183 | 0.045 | * |
Compound | Concentration [μM] | 24 h Incubation with Compounds [E/E0] | 1 h Incubation with Compounds [E/E0] | ||||
---|---|---|---|---|---|---|---|
With | With | ||||||
H2O2 | H2O2 | ||||||
Mean | SEM | p | Mean | SEM | p | ||
SIN-1 (incubated only 1 h) | 100 | 1.982 | 0.018 | * | 1.765 | 0.024 | * |
7a | 100 | 0.845 | 0.016 | * | 1.066 | 0.011 | * |
50 | 0.883 | 0.026 | * | 1.129 | 0.021 | ||
10 | 0.922 | 0.018 | * | 1.169 | 0.013 | ||
7b | 100 | 0.872 | 0.020 | * | 1.071 | 0.015 | |
50 | 0.832 | 0.038 | * | 1.114 | 0.033 | ||
10 | 0.832 | 0.028 | * | 1.229 | 0.023 | * | |
7c | 100 | 0.851 | 0.016 | * | 0.978 | 0.011 | |
50 | 0.840 | 0.010 | * | 0.964 | 0.005 | ||
10 | 0.834 | 0.010 | * | 0.906 | 0.005 | ||
7l | 100 | 0.977 | 0.014 | 0.995 | 0.009 | ||
50 | 0.902 | 0.012 | * | 0.931 | 0.004 | ||
10 | 0.842 | 0.039 | * | 0.853 | 0.022 | ||
7m | 100 | 0.912 | 0.013 | * | 0.923 | 0.011 | |
50 | 0.844 | 0.012 | * | 0.855 | 0.005 | ||
10 | 0.838 | 0.014 | * | 0.849 | 0.005 | ||
7n | 100 | 0.871 | 0.017 | * | 0.881 | 0.009 | |
50 | 0.802 | 0.008 | * | 0.813 | 0.007 | ||
10 | 0.790 | 0.008 | * | 0.801 | 0.034 |
Compound | Concentration [μM] | 24 h Incubation with Compounds [E/E0] | 1 h Incubation with Compounds [E/E0] | ||||
---|---|---|---|---|---|---|---|
With H2O2 | With H2O2 | ||||||
Mean | SEM | p | Mean | SEM | p | ||
H2O2 (incubated only 1 h) | 100 | 1.542 | 0.043 | * | 1.432 | 0.053 | * |
7a | 100 | 0.578 | 0.012 | * | 0.951 | 0.021 | |
50 | 0.581 | 0.022 | * | 0.958 | 0.011 | ||
10 | 0.599 | 0.031 | * | 0.967 | 0.012 | ||
7b | 100 | 0.545 | 0.041 | * | 0.911 | 0.021 | |
50 | 0.580 | 0.022 | * | 0.935 | 0.023 | ||
10 | 0.595 | 0.027 | * | 0.945 | 0.021 | ||
7c | 100 | 0.554 | 0.028 | * | 0.974 | 0.024 | |
50 | 0.561 | 0.012 | * | 1.002 | 0.021 | ||
10 | 0.571 | 0.015 | * | 1.054 | 0.041 | ||
7l | 100 | 0.603 | 0.022 | * | 1.065 | 0.027 | |
50 | 0.589 | 0.027 | * | 1.024 | 0.024 | ||
10 | 0.528 | 0.043 | * | 0.824 | 0.018 | * | |
7m | 100 | 0.642 | 0.065 | * | 1.373 | 0.014 | * |
50 | 0.561 | 0.054 | * | 1.324 | 0.024 | * | |
10 | 0.501 | 0.061 | * | 1.209 | 0.034 | * | |
7n | 100 | 0.822 | 0.042 | * | 1.302 | 0.024 | * |
50 | 0.565 | 0.044 | * | 1.246 | 0.031 | * | |
10 | 0.550 | 0.057 | * | 1.045 | 0.033 |
Compound | Concentration [μM] | 24 h Incubation with Compounds [E/E0] | 1 h Incubation with Compounds [E/E0] | ||||
---|---|---|---|---|---|---|---|
With | With | ||||||
H2O2 | H2O2 | ||||||
Mean | SEM | p | Mean | SEM | p | ||
SIN-1 (incubated only 1 h) | 100 | 1.987 | 0.110 | * | 2.021 | 0.51 | * |
7a | 100 | 0.827 | 0.005 | * | 0.815 | 0.007 | * |
50 | 0.843 | 0.007 | * | 0.838 | 0.009 | * | |
10 | 0.887 | 0.008 | * | 0.898 | 0.010 | * | |
7b | 100 | 0.982 | 0.044 | * | 0.954 | 0.061 | * |
50 | 0.877 | 0.007 | * | 0.849 | 0.024 | * | |
10 | 0.852 | 0.009 | * | 0.824 | 0.026 | * | |
7c | 100 | 1.042 | 0.014 | 1.014 | 0.031 | ||
50 | 1.049 | 0.026 | 1.019 | 0.026 | |||
10 | 1.039 | 0.024 | 1.012 | 0.031 | |||
7l | 100 | 1.085 | 0.009 | 1.043 | 0.016 | ||
50 | 1.054 | 0.019 | 1.026 | 0.026 | |||
10 | 0.992 | 0.019 | 1.019 | 0.026 | |||
7m | 100 | 1.047 | 0.029 | 1.093 | 0.036 | ||
50 | 1.054 | 0.006 | 1.046 | 0.013 | |||
10 | 1.033 | 0.005 | 1.033 | 0.012 | |||
7n | 100 | 1.180 | 0.007 | * | 1.048 | 0.017 | |
50 | 1.040 | 0.022 | 1.040 | 0.032 | |||
10 | 1.033 | 0.030 | 1.031 | 0.04 |
Quenching | Binding | Thermodynamic | |||||||
---|---|---|---|---|---|---|---|---|---|
T [K] | Ksv × 105 [dm3·mol−1] | kq × 1013 [dm3·mol−1·s−1] | logKb | Kb × 103 [dm3·mol−1] | n | ΔG° [kJmol−1] | ΔH° [kJmol−1] | ΔS° [Jmol−1 K−1] | |
7a | 297 303 308 | 1.60 ± 0.10 1.23 ± 0.18 0.63 ± 0.06 | 1.60 1.23 0.63 | 3.98 ± 0.09 2.93 ± 0.21 2.44 ± 0.30 | 9.12 0.85 0.27 | 0.79 ± 0.02 0.65 ± 0.05 0.61 ± 0.07 | −22.22 | −245.67 | −752.33 |
7b | 297 303 308 | 1.36 ± 0.18 1.13 ± 0.13 0.99 ± 0.14 | 1.36 1.13 0.99 | 3.66 ± 0.19 2.91 ± 0.22 2.49 ± 0.23 | 4.57 0.79 0.31 | 0.73 ± 0.05 0.62 ± 0.04 0.56 ± 0.03 | −20.62 | −187.54 | −562.03 |
7c | 297 303 308 | 1.63 ± 0.13 1.58 ± 0.10 1.33 ± 0.11 | 1.63 1.58 1.33 | 3.99 ± 0.13 3.69 ± 0.14 3.18 ± 0.14 | 9.77 4.90 1.51 | 0.78 ± 0.04 0.74 ± 0.02 0.66 ± 0.02 | −22.95 | −127.23 | −351.10 |
7l | 297 303 308 | 1.73 ± 0.10 1.09 ± 0.09 0.77 ± 0.08 | 1.73 1.09 0.77 | 3.22 ± 0.19 2.90 ± 0.21 2.54 ± 0.22 | 1.66 0.79 0.35 | 0.82 ± 0.03 0.62 ± 0.07 0.79 ± 0.04 | −18.41 | −109.07 | −295.15 |
7m | 297 303 308 | 0.29 ± 0.02 0.19 ± 0.01 0.09 ± 0.01 | 0.29 0.19 0.09 | 3.80 ± 0.17 3.07 ± 0.30 2.47 ± 0.32 | 6.31 1.18 0.30 | 0.88 ± 0.03 0.79 ± 0.05 0.75 ± 0.08 | −21.63 | −211.64 | −639.76 |
7n | 297 303 308 | 0.21 ± 0.01 0.18 ± 0.02 0.11 ± 0.01 | 0.21 0.18 0.11 | 3.75 ± 0.23 3.00 ± 0.24 2.35 ± 0.19 | 5.62 1.12 0.22 | 0.91 ± 0.05 0.78 ± 0.07 0.70 ± 0.04 | −21.47 | −222.00 | −675.18 |
Quenching | Binding | Thermodynamic | |||||||
---|---|---|---|---|---|---|---|---|---|
T [K] | Ksv × 104 [dm3·mol−1] | kq × 1012 [dm3·mol−1·s−1] | logKb | Kb × 103 [dm3·mol−1] | n | ΔG° [kJmol−1] | ΔH° [kJmol−1] | ΔS° [Jmol−1 K−1] | |
7a | 297 303 308 | 4.08 ± 0.20 3.44 ± 0.23 2.97 ± 0.17 | 4.08 3.44 2.97 | 3.89 ± 0.24 3.24 ± 0.20 2.73 ± 0.28 | 7.76 1.74 0.53 | 0.87 ± 0.04 0.77 ± 0.04 0.69 ± 0.05 | −22.18 | −186.27 | −552.71 |
7b | 297 303 308 | 3.08 ± 0.12 2.13 ± 0.17 1.77 ± 0.24 | 3.08 2.13 1.77 | 3.41 ± 0.21 2.65 ± 0.25 2.00 ± 0.32 | 1.57 0.45 0.10 | 0.81 ± 0.04 0.71 ± 0.04 0.61 ± 0.05 | −19.44 | −224.21 | −689.48 |
7c | 297 303 308 | 4.52 ± 0.31 4.19 ± 0.33 3.25 ± 0.39 | 4.52 4.19 3.25 | 3.39 ± 0.18 2.65 ± 0.21 2.31 ± 0.30 | 9.77 4.90 1.51 | 0.76 ± 0.03 0.65 ± 0.04 0.60 ± 0.07 | −19.05 | −175.20 | −525.78 |
7l | 297 303 308 | 2.50 ± 0.05 2.06 ± 0.10 1.16 ± 0.18 | 2.50 2.06 1.16 | 3.93 ± 0.18 3.31 ± 0.09 2.44 ± 0.31 | 8.32 2.04 0.28 | 0.92 ± 0.03 0.82 ± 0.02 0.69 ± 0.06 | −20.18 | −233.19 | −717.16 |
7m | 297 303 308 | 1.69 ± 0.10 1.45 ± 0.17 0.96 ± 0.11 | 1.69 1.45 0.96 | 3.42 ± 0.20 2.37 ± 0.29 2.00 ± 0.23 | 2.63 0.23 0.10 | 0.86 ± 0.03 0.68 ± 0.05 0.65 ± 0.04 | −19.00 | −229.09 | −707.36 |
7n | 297 303 308 | 1.83 ± 0.10 1.67 ± 0.09 1.40 ± 0.08 | 1.83 1.67 1.40 | 3.33 ± 0.23 3.06 ± 0.24 2.76 ± 0.21 | 2.14 1.15 0.56 | 0.84 ± 0.04 0.80 ± 0.04 0.75 ± 0.03 | −19.02 | −91.74 | −244.84 |
Site Marker | LogKb | |||||
---|---|---|---|---|---|---|
7a | 7b | 7c | 7l | 7m | 7n | |
- | 3.98 ± 0.09 | 3.66 ± 0.19 | 3.99 ± 0.13 | 3.22 ± 0.19 | 3.80 ± 0.17 | 3.75 ± 0.23 |
HSA+PHB (site I) | 3.00 ± 0.22 | 2.47 ± 0.20 | 3.20 ± 0.47 | 2.49 ± 0.17 | 3.07 ± 0.05 | 2.90 ± 0.40 |
HSA+IBP (site II) | 2.64 ± 0.07 | 2.71 ± 0.32 | 3.05 ± 0.36 | 2.13 ± 0.30 | 3.19 ± 0.16 | 2.51 ± 0.27 |
HSA: Analyzed Compound Molar Ratio | 7a | 7b | 7c | 7l | 7m | 7n |
---|---|---|---|---|---|---|
1:0 | 69.1% | 67.2% | 68.0% | 67.6% | 67.7% | 67.6% |
1:0.5 | 68.5% | 66.7% | 67.2% | 67.3% | 67.0% | 66.9% |
1:1 | 68.7% | 66.4% | 66.9% | 66.6% | 66.7% | 66.4% |
1:2 | 68.1% | 66.3% | 66.6% | 66.3% | 66.5% | 66.5% |
1:5 | 68.0% | 65.8% | 66.8% | 66.4% | 66.2% | 66.3% |
AAG: Analyzed Compound Molar Ratio | % α-Helix | % β-Sheet | % α-Helix | % β-Sheet |
---|---|---|---|---|
7a | 7b | |||
1:0 | 24.3% | 35.3% | 22.8% | 35.1% |
1:0.5 | 24.0% | 34.6% | 22.9% | 35.8% |
1:1 | 24.0% | 35.8% | 22.4% | 36.0% |
1:2 | 23.8% | 35.6% | 22.0% | 35.8% |
1:5 | 23.7% | 35.9% | 21.9% | 36.1% |
7c | 7l | |||
1:0 | 22.0% | 35.9% | 21.7% | 36.6% |
1:0.5 | 21.6% | 35.7% | 21.4% | 36.0% |
1:1 | 21.9% | 36.9% | 21.4% | 36.5% |
1:2 | 21.9% | 36.8% | 21.3% | 36.4% |
1:5 | 21.3% | 36.2% | 21.5% | 37.1% |
7m | 7n | |||
1:0 | 21.5% | 36.4% | 21.1% | 36.2% |
1:0.5 | 21.2% | 36.5% | 21.4% | 37.1% |
1:1 | 20.9% | 35.6% | 20.6% | 36.0% |
1:2 | 20.9% | 36.6% | 20.6% | 36.9% |
1:5 | 20.9% | 37.0% | 21.2% | 36.9% |
Amide I Ingredient Related to Structure | Free HSA | Complex HSA with Compound | |||||
---|---|---|---|---|---|---|---|
7a | 7b | 7c | 7l | 7m | 7n | ||
β-sheet (1610–1640 cm−1) | 25.42 | 29.47 | 25.75 | 26.39 | 26.42 | 28.18 | 25.69 |
random coil (1640–1650 cm−1) | 3.42 | 2.35 | 7.24 | 8.07 | 7.69 | 6.04 | 6.84 |
α-helix (1650–1665 cm−1) | 64.55 | 56.83 | 56.41 | 56.53 | 54.09 | 59.77 | 59.64 |
β-turn (1666–1673 cm−1) | 6.50 | 10.75 | 10.05 | 8.71 | 11.69 | 5.53 | 7.11 |
β-antiparallel (1675–1695 cm−1) | 0.11 | 0.60 | 0.55 | 0.30 | 0.11 | 0.48 | 0.72 |
Amide I Ingredient Related to Structure | Free AAG | Complex AAG with Compound | |||||
---|---|---|---|---|---|---|---|
7a | 7b | 7c | 7l | 7m | 7n | ||
β-sheet (1610–1640 cm−1) | 40.21 | 33.28 | 36.88 | 32.89 | 30.55 | 34.85 | 28.73 |
random coil (1640–1650 cm−1) | 15.33 | 20.28 | 18.62 | 25.63 | 26.13 | 23.57 | 31.41 |
α-helix (1650–1665 cm−1) | 25.02 | 30.06 | 26.95 | 25.09 | 26.63 | 25.80 | 25.92 |
β-turn (1666–1673 cm−1) | 9.64 | 11.40 | 9.20 | 11.74 | 12.51 | 8.12 | 11.40 |
β-antiparallel (1675–1695 cm−1) | 9.79 | 3.99 | 8.37 | 4.66 | 4.19 | 7.67 | 2.54 |
Compound | HSA | AAG | ||
---|---|---|---|---|
IIA (PHB) | IIA-IIB (IBU) | IIIA (IBU) | ||
7a | −6.7 | −8.9 | −5.6 | −9.7 |
7b | −8.4 | −8.2 | −6.0 | −8.1 |
7c | −5.6 | −8.9 | −1.9 | −9.2 |
7l | −6.9 | −7.6 | −7.3 | −8.6 |
7m | −8.2 | −7.4 | −6.3 | −8.3 |
7n | −7.7 | −8.3 | −7.1 | −8.5 |
Compound | Physicochemical Properties—Lipinski’s Rule of Five (Ro5) | ||||
---|---|---|---|---|---|
#H-Bond Acceptors | #H-Bond Donors | Log Po/w (MLOGP) | MW [g/mol] | #Violations | |
7a | 3 | 0 | 3.38 | 414.50 | 0 |
7b | 3 | 0 | 2.91 | 394.51 | 0 |
7c | 3 | 0 | 3.85 | 448.94 | 0 |
7l | 6 | 0 | 1.33 | 416.49 | 0 |
7m | 6 | 0 | 0.82 | 396.50 | 0 |
7n | 6 | 0 | 1.82 | 450.94 | 0 |
Compound | Pharmacokinetics | |||
---|---|---|---|---|
GI Absorption | BBB Permeability | P-gp Substrate | Water Solubility | |
7a | High | Yes | Yes | Poorly soluble |
7b | High | Yes | No | Moderately soluble |
7c | High | Yes | No | Poorly soluble |
7l | High | No | No | Moderately soluble |
7m | High | No | No | Soluble |
7n | High | No | No | Moderately soluble |
Compound | Drug-Likeness | |||
---|---|---|---|---|
Lipinski | Veber | Bioavailability Score | TPSA [Å2] | |
7a | Yes, 0 violation | Yes | 0.55 | 50.48 |
7b | Yes, 0 violation | Yes | 0.55 | 50.48 |
7c | Yes, 0 violation | Yes | 0.55 | 50.48 |
7l | Yes, 0 violation | Yes | 0.55 | 93.00 |
7m | Yes, 0 violation | Yes | 0.55 | 93.00 |
7n | Yes, 0 violation | Yes | 0.55 | 93.00 |
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Szczukowski, Ł.; Maniewska, J.; Wiatrak, B.; Jawień, P.; Krzyżak, E.; Kotynia, A.; Marciniak, A.; Janeczek, M.; Redzicka, A. Interactions of N-Mannich Bases of Pyrrolo[3,4-c]pyrrole with Artificial Models of Cell Membranes and Plasma Proteins, Evaluation of Anti-Inflammatory and Antioxidant Activity. Membranes 2023, 13, 349. https://doi.org/10.3390/membranes13030349
Szczukowski Ł, Maniewska J, Wiatrak B, Jawień P, Krzyżak E, Kotynia A, Marciniak A, Janeczek M, Redzicka A. Interactions of N-Mannich Bases of Pyrrolo[3,4-c]pyrrole with Artificial Models of Cell Membranes and Plasma Proteins, Evaluation of Anti-Inflammatory and Antioxidant Activity. Membranes. 2023; 13(3):349. https://doi.org/10.3390/membranes13030349
Chicago/Turabian StyleSzczukowski, Łukasz, Jadwiga Maniewska, Benita Wiatrak, Paulina Jawień, Edward Krzyżak, Aleksandra Kotynia, Aleksandra Marciniak, Maciej Janeczek, and Aleksandra Redzicka. 2023. "Interactions of N-Mannich Bases of Pyrrolo[3,4-c]pyrrole with Artificial Models of Cell Membranes and Plasma Proteins, Evaluation of Anti-Inflammatory and Antioxidant Activity" Membranes 13, no. 3: 349. https://doi.org/10.3390/membranes13030349