An Effective, Green Synthesis Procedure for Obtaining Coumarin–Hydroxybenzohydrazide Derivatives and Assessment of Their Antioxidant Activity and Redox Status
Abstract
:1. Introduction
2. Materials and Methods
2.1. Chemical Reagents and Instruments
2.2. Synthesis of Coumarin–Hydroxybenzohydrazide Derivatives
2.3. In Vitro Tests for the Assessment of Antioxidant Activity
2.3.1. DPPH Radical Scavenging Assay
2.3.2. ABTS Radical Scavenging Assay
2.3.3. Ferric Reducing Antioxidant Power (FRAP) Assay
2.4. In Vitro Determination of Anticancer Activity
2.4.1. Cytotoxic Effects of Coumarins
2.4.2. Effects of Coumarins on Redox Status in Cancer Cells
Superoxide Anion Level (O2˙−)
Damage to Membrane Lipids
Glutathione Level (GSH)
2.5. Computational Methodology
2.6. Statistical Analysis
3. Results and Discussion
3.1. Synthesis and Structural Characterization of Novel Coumarin–Hydroxybenzohydrazide Derivatives (C-HB1 and C-HB2)
3.2. In Vitro Radical Scavenging Ability of Coumarin–Hydroxybenzohydrazide Derivatives
3.2.1. Antioxidant Activity of C-HBs against DPPH Radical
3.2.2. Antioxidant Activity of C-HBs against ABTS Radical Cation
3.2.3. Ferric Reducing Antioxidant Power of C-HBs
3.3. Anticancer Properties of Coumarin–Hydroxybenzohydrazide Derivatives
3.3.1. Cytotoxicity
3.3.2. Effects of Coumarins on Redox Status in Cancer Cells
3.4. Determination of the Plausible Mechanisms of Antiradical Activity of Coumarin–Hydroxybenzohydrazide Derivatives
3.4.1. Investigation of Radical Scavenging Mechanism towards DPPH Radical
3.4.2. Investigation of Radical Scavenging Mechanism towards ABTS Radical Cation
3.5. ADMET Analysis
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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Compound | DPPH Scavenging Ability (%) | IC50 (µM) | SF | |||||
---|---|---|---|---|---|---|---|---|
25 µM | 50 µM | 100 µM | ||||||
20 min | 60 min | 20 min | 60 min | 20 min | 60 min | |||
C–HB1 | 82.5 ± 0.8 | 85.2 ± 1.0 | 86.9 ± 0.6 | 88.5 ± 0.7 | 89.1 ± 1.0 | 90.1 ± 0.6 | 6.4 ± 0.1 | 2.0 |
C–HB2 | 92.5 ± 1.2 | 93.0 ± 1.2 | 93.6 ± 0.5 | 93.8 ± 0.4 | 94.0 ± 0.8 | 94.1 ± 0.6 | 2.5 ± 0.1 | 5.0 |
NDGA | 94.6 ± 0.7 | 94.6 ± 0.6 | 94.2 ± 0.7 | 94.2 ± 0.7 | 94.5 ± 0.2 | 94.1 ± 0.7 | 1.7 ± 0.1 | 7.4 |
Gallic acid | 93.4 ± 0.8 | 93.5 ± 0.6 | 94.5 ± 0.9 | 94.3 ± 0.7 | 97.1± 1.1 | 97.0± 0.9 | 2.6 ± 0.2 | 4.8 |
Compound | ABTS Radical Cation Scavenging Activity | ||||||
---|---|---|---|---|---|---|---|
Scavenging Ability (%) | IC50 (µM) | ||||||
1 µM | 2 µM | 3 µM | 4 µM | 6 µM | 8 µM | ||
C–HB1 | - | - | - | 47.9 ± 1.7 | 55.3 ± 0.9 | 64.7 ± 1.4 | 4.5 ± 0.1 |
C–HB2 | 20.4 ± 1.8 | 46.7 ± 0.9 | 68.9 ± 0.3 | - | - | - | 2.0 ± 0.2 |
Trolox | - | - | - | 38.8 ± 2.1 | 55.3 ± 2.2 | 71.9 ± 2.6 | 5.3 ± 0.1 |
Compounds | Absorbance 700 nm |
---|---|
C–HB1 | 0.3979 ± 0.0092 |
C–HB2 | 0.7725 ± 0.0242 |
Ascorbic acid | 0.1249 ± 0.0022 |
Compounds | IC50 (μM) | |
---|---|---|
24 h | 72 h | |
C–HB1 | 154.42 ± 0.12 | 104.86 ± 0.05 |
C–HB2 | 102.96 ± 0.06 | 54.49 ± 0.07 |
Compounds | Position | Mechanisms | ||
---|---|---|---|---|
HAT | SET | PT | ||
ΔrGHAT | ΔrGSET | ΔrGPT | ||
C–HB1 | 2-OH | 13 | 159 | −146 |
3-OH | 9 | −150 | ||
4-OH | 31 | −127 | ||
N2-H | 23 | −136 | ||
C–HB2 | 3-OH/5-OH | 19 | 165 | −146 |
4-OH | −1 | −166 | ||
N2-H | 28 | −137 |
Compounds | Position | Mechanisms | ||
---|---|---|---|---|
HAT | SET | PT | ||
ΔrGHAT | ΔrGSET | ΔrGPT | ||
C–HB1 | 2-OH | 29 | −116 | 145 |
3-OH | 25 | 141 | ||
4-OH | 47 | 163 | ||
N2-H | 38 | 154 | ||
C–HB2 | 3-OH/5-OH | 35 | −110 | 144 |
4-OH | 15 | 124 | ||
N2-H | 44 | 153 |
Compounds | Absorption | Distribution | ||||||
---|---|---|---|---|---|---|---|---|
Caco-2p (cm s−1) | MDCK (cm s−1) | HIA | F20% | F30% | PPS % | Fu % | VD (L kg−1) | |
C–HB1 | −5.282 | 1.40 × 10−6 | 0.095 | 0.364 | 0.042 | 99.08 | 5.650 | 0.556 |
C–HB2 | −5.853 | 7.20 × 10−6 | 0.103 | 0.578 | 0.085 | 97.90 | 6.270 | 0.551 |
Vitamin C | −5.917 | 1.40 × 10−4 | 0.069 | 0.918 | 0.987 | 63.23 | 36.58 | 0.937 |
Gallic acid | −5.728 | 5.10 × 10−6 | 0.085 | 0.964 | 0.995 | 53.49 | 33.59 | 0.446 |
Compounds | Metabolism; P450 | Elimination | ||||||
---|---|---|---|---|---|---|---|---|
1A2 | 3A4 | 2C9 | T1/2 h | CL mL min−1 kg−1 | ||||
I | S | I | S | I | S | |||
C-HB1 | 0.269 | 0.062 | 0.027 | 0.043 | 0.314 | 0.089 | 0.953 | 1.125 |
C-HB2 | 0.304 | 0.063 | 0.025 | 0.040 | 0.390 | 0.138 | 0.951 | 1.227 |
Vitamin C | 0.013 | 0.052 | 0.010 | 0.057 | 0.007 | 0.230 | 0.928 | 9.964 |
Gallic acid | 0.023 | 0.075 | 0.026 | 0.039 | 0.188 | 0.061 | 0.947 | 10.108 |
Compounds | hERG | H-HT | AMES | RT |
---|---|---|---|---|
C-HB1 | 0.006 | 0.195 | 0.094 | 0.240 |
C-HB2 | 0.007 | 0.196 | 0.045 | 0.303 |
Vitamin C | 0.015 | 0.168 | 0.027 | 0.096 |
Gallic acid | 0.017 | 0.443 | 0.053 | 0.381 |
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Avdović, E.H.; Milanović, Ž.; Simijonović, D.; Antonijević, M.; Milutinović, M.; Nikodijević, D.; Filipović, N.; Marković, Z.; Vojinović, R. An Effective, Green Synthesis Procedure for Obtaining Coumarin–Hydroxybenzohydrazide Derivatives and Assessment of Their Antioxidant Activity and Redox Status. Antioxidants 2023, 12, 2070. https://doi.org/10.3390/antiox12122070
Avdović EH, Milanović Ž, Simijonović D, Antonijević M, Milutinović M, Nikodijević D, Filipović N, Marković Z, Vojinović R. An Effective, Green Synthesis Procedure for Obtaining Coumarin–Hydroxybenzohydrazide Derivatives and Assessment of Their Antioxidant Activity and Redox Status. Antioxidants. 2023; 12(12):2070. https://doi.org/10.3390/antiox12122070
Chicago/Turabian StyleAvdović, Edina H., Žiko Milanović, Dušica Simijonović, Marko Antonijević, Milena Milutinović, Danijela Nikodijević, Nenad Filipović, Zoran Marković, and Radiša Vojinović. 2023. "An Effective, Green Synthesis Procedure for Obtaining Coumarin–Hydroxybenzohydrazide Derivatives and Assessment of Their Antioxidant Activity and Redox Status" Antioxidants 12, no. 12: 2070. https://doi.org/10.3390/antiox12122070