Potential COVID-19 Drug Candidates Based on Diazinyl-Thiazol-Imine Moieties: Synthesis and Greener Pastures Biological Study
Abstract
:1. Introduction
2. Results and Discussions
2.1. Molecular Modeling against 7BQY
2.2. In Silico Toxicity Prediction for Compounds 3a–f
2.3. Drug Likeness Evaluation
3. Materials and Methods
3.1. Instruments
3.2. Synthesis of 2-Amino-4-phenyl-5-arylazothiazoles
3.3. General Procedure for the Synthesis of Compounds 3a–f
3.4. Docking In Silico Studies
3.5. Statistical Analysis
3.6. In Silico Toxicity Prediction
3.7. SwissADME Drug-Likeness Properties Prediction
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Sample Availability
References
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Source of Variance | DF | F-Value | p-Value |
---|---|---|---|
Ligands and approved drugs | 7 | 7.42 | 0.00 |
Number of poses | 8 | 7.12 | 0.00 |
Ligand and Approved Medicines | Average Binding Energy (kcal/mol) | |
---|---|---|
Ligands | 3f | −7.81 ± 0.48 a |
3d | −7.52 ± 0.21 a,b | |
3a | −7.41 ± 0.29 a,b,c | |
3b | −7.36 ± 0.50 a,b,c | |
3e | −7.25 ± 0.46 a,b,c,d | |
3c | −7.13 ± 0.46 b,c,d | |
Approved medicine | Remdesivir | −6.93 ± 0.33 c,d |
Molnupiravir | −6.71 ± 0.23 d |
Ligand | Oral Toxicity Prediction Results | |||
---|---|---|---|---|
Predicted LD50 (mg/kg) | Predicted Toxicity Class | Average Similarity (%) | Prediction Accuracy (%) | |
3a | 300 | 3 | 44.61 | 54.26 |
3b | 300 | 3 | 42.28 | 54.26 |
3c | 300 | 3 | 44.32 | 54.26 |
3d | 300 | 3 | 45.74 | 54.26 |
3e | 1000 | 4 | 43.73 | 54.26 |
3f | 1000 | 4 | 42.98 | 54.26 |
Molnupiravir | 1000 | 4 | 40.93 | 54.26 |
Remdesivir | 826 | 4 | 79.41 | 69.26 |
Ligands | Hepatotoxicity | Carcinogenicity | Immunotoxicity | Mutagenicity | Cytotoxicity | |||||
---|---|---|---|---|---|---|---|---|---|---|
Activity | Probability | Activity | Probability | Activity | Probability | Activity | Probability | Activity | Probability | |
3a | Yes | 0.58 | Yes | 0.59 | No | 0.99 | Yes | 0.57 | No | 0.80 |
3b | Yes | 0.55 | Yes | 0.77 | No | 0.99 | Yes | 0.75 | No | 0.76 |
3c | Yes | 0.55 | Yes | 0.60 | No | 0.99 | Yes | 0.58 | No | 0.82 |
3d | Yes | 0.57 | No | 0.59 | No | 0.99 | No | 0.55 | No | 0.82 |
3e | Yes | 0.58 | Yes | 0.57 | No | 0.99 | Yes | 0.63 | No | 0.73 |
3f | Yes | 0.58 | Yes | 0.57 | No | 0.99 | Yes | 0.63 | No | 0.73 |
Molnupiravir | Yes | 0.56 | No | 0.50 | No | 0.96 | No | 0.50 | No | 0.74 |
Remdesivir | No | 0.56 | No | 0.55 | No | 0.90 | No | 0.62 | No | 0.55 |
Physicochemical | 3a | 3b | 3c | 3d | 3e | 3f | Molnupiravir | Remdesivir |
---|---|---|---|---|---|---|---|---|
Molecular weight (g/mol) | 368.45 | 429.45 | 382.48 | 416.93 | 412.51 | 412.51 | 329.31 | 602.58 |
Heavy atom | 27 | 31 | 28 | 29 | 30 | 30 | 23 | 42 |
Arom. heavy atom | 23 | 23 | 23 | 23 | 23 | 23 | 6 | 15 |
Fraction Csp3 | 0.00 | 0.00 | 0.04 | 0.04 | 0.08 | 0.08 | 0.62 | 0.48 |
Rotatable bond | 5 | 6 | 5 | 5 | 6 | 6 | 6 | 14 |
H-bond acceptor | 4 | 7 | 4 | 4 | 5 | 5 | 8 | 12 |
H-bond donor | 0 | 1 | 0 | 0 | 0 | 0 | 4 | 4 |
Molar refractivity | 111.86 | 122.71 | 116.83 | 121.84 | 123.32 | 123.32 | 76.02 | 150.43 |
Polar surface area (Å2) | 78.21 | 144.26 | 78.21 | 78.21 | 87.44 | 87.44 | 143.14 | 213.36 |
Lipophilicity | ||||||||
MLOGP | 4.05 | 2.57 | 4.27 | 4.74 | 3.92 | 3.92 | −1.15 | 0.18 |
WLOGP | 6.98 | 6.59 | 7.28 | 7.94 | 7.29 | 7.29 | −1.65 | 2.21 |
XLOGP3 | 6.36 | 5.83 | 6.72 | 7.35 | 6.69 | 6.69 | −1.34 | 1.91 |
Drug-likeness evaluation | ||||||||
Lipinski | 0 | 0 | 1 | 1 | 0 | 0 | 0 | 2 |
Pharmacokinetics | 3a | 3b | 3c | 3d | 3e | 3f | Molnupiravir | Remdesivir | |
---|---|---|---|---|---|---|---|---|---|
Gastrointestinal (GI) absorption | Low | Low | Low | Low | Low | Low | Low | Low | |
Blood–brain barrier (BBB) permeant | No | No | No | No | No | No | No | No | |
P-glycoprotein (P-gp) substrate | No | No | No | Yes | No | No | No | Yes | |
Inhibitor | CYP1A2 | Yes | No | No | No | No | No | No | No |
CYP2C19 | Yes | No | Yes | No | No | No | No | No | |
CYP2C9 | Yes | Yes | Yes | No | Yes | Yes | Yes | No | |
CYP2D6 | No | No | No | No | No | No | No | No | |
CYP3A4 | No | No | No | No | No | No | No | Yes |
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Abu-Melha, S.; Edrees, M.M.; Said, M.A.; Riyadh, S.M.; Al-Kaff, N.S.; Gomha, S.M. Potential COVID-19 Drug Candidates Based on Diazinyl-Thiazol-Imine Moieties: Synthesis and Greener Pastures Biological Study. Molecules 2022, 27, 488. https://doi.org/10.3390/molecules27020488
Abu-Melha S, Edrees MM, Said MA, Riyadh SM, Al-Kaff NS, Gomha SM. Potential COVID-19 Drug Candidates Based on Diazinyl-Thiazol-Imine Moieties: Synthesis and Greener Pastures Biological Study. Molecules. 2022; 27(2):488. https://doi.org/10.3390/molecules27020488
Chicago/Turabian StyleAbu-Melha, Sraa, Mastoura Mohamed Edrees, Musa A. Said, Sayed M. Riyadh, Nadia S. Al-Kaff, and Sobhi M. Gomha. 2022. "Potential COVID-19 Drug Candidates Based on Diazinyl-Thiazol-Imine Moieties: Synthesis and Greener Pastures Biological Study" Molecules 27, no. 2: 488. https://doi.org/10.3390/molecules27020488