Structure Activity Relationship and Molecular Docking of Some Quinazolines Bearing Sulfamerazine Moiety as New 3CLpro, cPLA2, sPLA2 Inhibitors
Abstract
:1. Introduction
2. Results
2.1. Chemistry
2.2. Biological Studies
2.2.1. CLpro Inhibitory Activity of Synthesized Compounds 4–6 and 12
2.2.2. sPLA2 Inhibitory Activity of Synthesized Compounds 4–6, and 12
2.2.3. cPLA2 Inhibitory Activity of Synthesized Compounds 4–6 and 12
2.2.4. Effects of Compounds 4–6, and 12 as well as Baicalein and Ivermectin on sPLA2, cPLA2, IL-8, TNF-α, and NO in Isolated Lung Cells Treated with LPS
2.2.5. In Silico Studies
Drug Likeliness
ADMET Prediction
3. Discussion
3.1. Chemistry
3.2. Biological Studies
Effects of Compounds 4–6 and 12 as well as Baicalein and Ivermectin on sPLA2, cPLA2, IL-8, TNF-α, and NO in Isolated Lung Cells Treated with LPS
3.3. Molecular Docking (MD) Simulations
ADMET Prediction
4. Materials and Methods
4.1. Chemistry
4.1.1. Synthesis and Characterization of Methyl-2-Isothiocyanato Benzoic Acid
4.1.2. Synthesis and Characterization of Compound 3
4.1.3. Synthesis and Characterization of Compound 4
4.1.4. Synthesis and Characterization of Compound 5
4.1.5. Synthesis and Characterization of Compounds 6 and 12
4.2. Biological Testing
4.2.1. 3CLpro Enzyme Inhibition Assay
4.2.2. sPLA2 Enzyme Inhibition Assay
4.2.3. cPLA2 Enzyme Inhibition Assay
4.2.4. Inhibition by Synthesized Compounds (4–6 and 12) as well as Baicalein and Ivermectin against cPLA2 and sPLA2 in LPS-Treated Mouse Lung Cells
4.3. Molecular Docking
4.3.1. Molecular Docking (MD) Simulations
4.3.2. ADMET Prediction
4.4. Statistical Analysis
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Sample Availability
Abbreviations
References
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Synthesized Compounds/Drugs | SARS-CoV-2 Main Protease (µM) | sPLA2 (µM) | cPLA2 (µM) |
---|---|---|---|
Compound 4 | 2.012 ± 0.004 c | 2.84 ± 0.026 c | 1.44 ± 0.009 b |
Compound 5 | 3.68 ± 2.35 d | 2.73 ± 0.008 c | 2.08 ± 0.016 c |
Compound 6 | 1.180 ± 0.025 a | 1.016 ± 0.039 b | 0.5 ± 0.008 a |
Compound 12 | 5.47 ± 0.018 e | 4.45 ± 0.007 d | 2.39 ± 0.046 d |
Baicalein | 1.72 ± 0.006 b | 0.89 ± 0.041 a | 3.88 ± 0.013 e |
Ivermectin | 42.39 ± 2.50 f | 109.6 ± 3.27 e | 138.0 ± 1.54 f |
Group No. | Synthesized Compounds/Drugs | Doses | sPLA2 (pg/mL) | cPLA2 (dpm/mL) | IL-8 (ng/mL) | TNF-α (pg/mL) | NO (µmol/L) |
---|---|---|---|---|---|---|---|
I | Negative control sample | 0 μg/ML | 12.59 ± 0.46 a | 474.22 ± 25.21 a | 0.82 ± 0.08 a | 476.97 ± 32.77 a | 17.79 ± 2.16 a |
II | Positive control (LPS) | (1 μg/mL) | 129.58 ± 6.34 n | 2817.86 ± 40.51 l | 5.74 ± 0.47 h | 980.27 ± 75.96 l | 68.59 ± 5.82 j |
III | LPS (1 μg/mL) + Compound 4 | 1.44 µM | 57.93 ± 2.92 i | 1077.77 ± 68.61 i | 2.55 ± 0.26 c | 654.20 ± 22.28 h | 37.27 ± 3.00 c |
2.84 µM | 29.10 ± 2.52 d | 671.05 ± 29.17 d | 2.17 ± 0.07 d | 481.36 ± 39.63 d | 25.18 ± 2.98 d | ||
IV | LPS (1 μg/mL) + Compound 5 | 2.08 µM | 72.13 ± 3.94 k | 1258.99 ± 35.57 k | 2.74 ± 0.32 c | 671.91 ± 23.11 i | 45.75 ± 2.87 g |
3.68 µM | 34.17 ± 1.73 e | 719.32 ± 37.15 e | 2.40 ±0.09 e | 524.98 ± 19.11 e | 29.37 ± 2.21 f | ||
V | LPS (1 μg/mL) + Compound 6 | 0.5 µM | 43.44 ± 2.74 g | 830.11 ± 34.00 f | 1.79 ± 0.14 d | 582.31 ± 52.25 e | 24.67 ± 2.70 e |
1.18 µM | 18.29 ± 2.35 b | 536.93 ± 23.50 b | 1.17 ± 0.06 b | 424.25 ± 36.86 f | 19.02 ± 1.5 b | ||
VI | LPS (1 μg/mL) + Compound 12 | 2.39 µM | 85.23 ± 6.51 l | 1348.21 ± 50.26 | 3.84 ± 0.29 g | 748.98 ± 31.22 j | 50.36 ± 3.96 h |
5.47 µM | 40.61 ± 4.19 f | 722.24 ± 30.40 e | 3.21 ± 0.21 f | 551.52 ± 24.65 f | 30.94 ± 3.76 f | ||
VII | LPS (1 μg/mL) + Baicalein | 0.89 µM | 54.27 ± 3.46 h | 903.43 ± 35.71 g | 2.06 ± 0.23 g | 639.55 ± 37.84 g | 32.01 ± 4.81 f |
3.88 µM | 24.77 ± 2.73 c | 616.34 ± 28.34 c | 1.42 ± 0.13 c | 431.21 ± 32.88 c | 20.53 ± 1.89 c | ||
VIII | LPS (1 μg/mL) + Ivermectin | 131.01 µM | 106.13 ± 9.81 m | 1172.50 ± 72.55 j | 3.77 ± 0.62 g | 870.22 ± 40.62 k | 62.01 ± 4.81 i |
149.39 µM | 62.31 ± 1.41 j | 1002.65 ± 90.98 h | 3.10 ± 0.1 f | 714.29 ± 28.09 g | 50.74 ± 3.34 h |
CPDS | SARS-CoV-2 Main Protease (3CLpro) (PDB = 5RFS) # | Phospholipase A2 (sPLA2) (PDB = 1DCY) | Cytosolic Phospholipase A2 (cPLA2) (PDB = 1CJY) | |||
---|---|---|---|---|---|---|
Binding Energy (Kcal/mol) | Binding Interactions | Binding Energy (Kcal/mol) | Binding Interactions | Binding Energy (Kcal/mol) | Binding Interactions | |
2 | −12.92 | 1 H-bond with Gly 143 pi–pi interaction with His 41 | −13.19 | 1 H-bond with His 47 | −7.22 | Cation–arene interaction with Tyr 96 |
3 | −19.91 | 1 H-bond with Gly 143 | −11.43 | 1 H-bond with His 47 | −11.17 | pi–pi interaction with Tyr 96 |
4 | −26.06 | 1 H-bond with Gly 143 | −22.33 | 1 H-bond with His 47 | −17.82 | pi–pi interaction with Tyr 96 |
5 | −25.83 | 1 H-bond with Gly 143 | −23.57 | 1 H-bond with His 47 | −13.77 | pi–pi interaction with Tyr 96 |
6 | −23.14 | 1 H-bond with Gly 143 | −18.38 | 1 H-bond with His 47 | −9.99 | pi–pi interaction with Tyr 96 |
12 | −23.28 | 1 H-bond with Gly 143 pi–pi interaction with His 41 | −23.49 | 1 H-bond with His 47 | −12.84 | pi–pi interaction with Tyr 96 |
Ivermectin | −23.37 | -- | −6.09 | -- | −16.63 | -- |
Baicalein | −15.07 | 1 H-bond with Gly 143 | −18.24 | 2 H-bond with His 47 | −15.54 | -- |
Comp. No | MW g/mol | Log p | HBA | HBD | TPSA Å2 | MR | nRB | No. Lipinski Violations |
---|---|---|---|---|---|---|---|---|
2 | 193.22 | 2.88 | 3 | 0 | 70.75 | 52.41 | 3 | 0 |
3 | 457.53 | 2.35 | 6 | 3 | 162.78 | 121.31 | 9 | 0 |
4 | 423.45 | 1.18 | 6 | 3 | 153.27 | 113.36 | 5 | 0 |
5 | 557.58 | 2.90 | 9 | 3 | 169.07 | 151.17 | 8 | 2 |
6 | 463.47 | 1.19 | 7 | 2 | 147.56 | 127.12 | 4 | 1 |
12 | 505.51 | 2.09 | 9 | 1 | 158.82 | 129.85 | 7 | 2 |
Models | 2 | 3 | 4 | 5 | 6 | 12 |
---|---|---|---|---|---|---|
Blood–Brain Barrier | BBB+ | BBB− | BBB+ | BBB− | BBB+ | BBB− |
Human Intestinal Absorption | HIA+ | HIA+ | HIA+ | HIA+ | HIA+ | HIA+ |
Caco-2 Permeability | Caco-2- | Caco-2- | Caco-2- | Caco-2- | Caco-2- | Caco-2- |
Aqueous solubility (Log S) | −2.8928 | −3.2434 | −3.1843 | −3.3822 | −3.5571 | −3.9130 |
P-glycoprotein Substrate | Non-substrate | Non-substrate | Non-substrate | Non-substrate | Substrate | Non-substrate |
P-glycoprotein Inhibitor I | Non-inhibitor | Non-inhibitor | Non-inhibitor | Non-inhibitor | Non-inhibitor | Non-inhibitor |
P-glycoprotein Inhibitor II | Non-inhibitor | Non-inhibitor | Non-inhibitor | Inhibitor | Non-inhibitor | Non-inhibitor |
Renal Organic Cation Transporter | Non-inhibitor | Non-inhibitor | Non-inhibitor | Non-inhibitor | Non-inhibitor | Non-inhibitor |
Subcellular localization | Mitochondria | Mitochondria | Mitochondria | Mitochondria | Mitochondria | Mitochondria |
CYP450 2C9 Substrate | Non-Substrate | Non-Substrate | Non-Substrate | Non-Substrate | Non-Substrate | Non-Substrate |
CYP450 2D6 Substrate | Non-Substrate | Non-Substrate | Non-Substrate | Non-Substrate | Non-Substrate | Non-Substrate |
CYP450 3A4 Substrate | Non-Substrate | Non-substrate | Non-substrate | Non-substrate | Substrate | Non-substrate |
CYP450 1A2 Inhibitor | Inhibitor | Non-inhibitor | Non-inhibitor | Non-inhibitor | Non-inhibitor | Non-inhibitor |
CYP450 2D6 Inhibitor | Non-inhibitor | Non-inhibitor | Non-inhibitor | Non-inhibitor | Non-inhibitor | Non-inhibitor |
CYP450 3A4 Inhibitor | Non-inhibitor | Non-inhibitor | Non-inhibitor | Non-inhibitor | Non-inhibitor | Inhibitor |
CYP450 2C19 Inhibitor | Non-inhibitor | Non-inhibitor | Non-inhibitor | Non-inhibitor | Non-inhibitor | Non-inhibitor |
Human Ether-a-go-go-Related Gene Inhibition I | Weak inhibitor | Weak inhibitor | Weak inhibitor | Weak inhibitor | Weak inhibitor | Weak inhibitor |
Human Ether-a-go-go Related Gene Inhibition II | Non-inhibitor | Non-inhibitor | Non-inhibitor | Non-inhibitor | Non-inhibitor | Non-inhibitor |
AMES Toxicity | Non AMES toxic | Non AMES toxic | Non AMES toxic | Non AMES toxic | Non AMES toxic | Non AMES toxic |
Carcinogens | Non-carcinogen | Non-carcinogen | Non-carcinogen | Non-carcinogen | Non-carcinogen | Non-carcinogen |
Honeybee toxicity | High HBT | Low HBT | Low HBT | Low HBT | Low HBT | Low HBT |
Biodegradation | Not readily biodegradable | Not readily biodegradable | Not readily biodegradable | Not readily biodegradable | Not readily biodegradable | Not readily biodegradable |
Acute oral toxicity | III | III | III | III | III | III |
Carcinogenicity (three class) | Non-required | Non-required | Non-required | Non-required | Non-required | Non-required |
Rat Acute Toxicity (LD50, mol/kg) | 2.2363 | 2.1081 | 2.0649 | 2.2374 | 2.2163 | 2.4056 |
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Hussein, M.A.; Borik, R.M.; Nafie, M.S.; Abo-Salem, H.M.; Boshra, S.A.; Mohamed, Z.N. Structure Activity Relationship and Molecular Docking of Some Quinazolines Bearing Sulfamerazine Moiety as New 3CLpro, cPLA2, sPLA2 Inhibitors. Molecules 2023, 28, 6052. https://doi.org/10.3390/molecules28166052
Hussein MA, Borik RM, Nafie MS, Abo-Salem HM, Boshra SA, Mohamed ZN. Structure Activity Relationship and Molecular Docking of Some Quinazolines Bearing Sulfamerazine Moiety as New 3CLpro, cPLA2, sPLA2 Inhibitors. Molecules. 2023; 28(16):6052. https://doi.org/10.3390/molecules28166052
Chicago/Turabian StyleHussein, Mohammed Abdalla, Rita M. Borik, Mohamed S. Nafie, Heba M. Abo-Salem, Sylvia A. Boshra, and Zahraa N. Mohamed. 2023. "Structure Activity Relationship and Molecular Docking of Some Quinazolines Bearing Sulfamerazine Moiety as New 3CLpro, cPLA2, sPLA2 Inhibitors" Molecules 28, no. 16: 6052. https://doi.org/10.3390/molecules28166052
APA StyleHussein, M. A., Borik, R. M., Nafie, M. S., Abo-Salem, H. M., Boshra, S. A., & Mohamed, Z. N. (2023). Structure Activity Relationship and Molecular Docking of Some Quinazolines Bearing Sulfamerazine Moiety as New 3CLpro, cPLA2, sPLA2 Inhibitors. Molecules, 28(16), 6052. https://doi.org/10.3390/molecules28166052