Strong Inhibitory Activity and Action Modes of Synthetic Maslinic Acid Derivative on Highly Pathogenic Coronaviruses: COVID-19 Drug Candidate
Abstract
:1. Introduction
2. Results and Discussion
2.1. Chemistry
2.1.1. Green Chemistry Extraction of Compounds 1 and 2
2.1.2. Synthesis
2.2. Anti-SARS-CoV-2 Activity
2.2.1. Molecular Docking Studies
2.2.2. Compound 17 Showed Promising Anti-SARS-CoV-2 Activity at Non-Toxic Concentrations
2.2.3. Compound 17 Showed Promising Anti-MERS-CoV Activity and Non-Toxic Concentrations
2.2.4. Structure–Activity Relationship (SAR) Study
- (a)
- The common shared steroidal nucleus of the selected tested compounds (1–17) appeared to be very promising for their antiviral activities. Molecular docking revealed the great stabilization of the tested compounds inside the branched large pocket of SARS-CoV-2 main protease as a proposed mechanism of action.
- (b)
- The presence of OH groups at positions 2 and 3 of the steroidal nucleus seems to be very crucial for the antiviral activity. Most compounds (17, 3, and 10) containing both 2- and 3-OH groups achieved high to moderate activities (4.12–99.87 µM). Docking studies referred to the involvement of both OH groups in hydrogen bond formations with Thr24 and/or Thr26 amino acids of the binding pocket.
- (c)
- Compound (17) containing the isoxazole side chain with a p-chlorophenyl substitution (an electron withdrawing lipophilic group) achieved a very high cytotoxic activity (IC50 = 4.12 µM). However, both compounds (16 and 15) containing the isoxazole side chain with a p-methoxyphenyl substitution (an electron donating hydrophilic group) achieved low cytotoxic activities (IC50 = 218.8 and 523 µM, respectively). Therefore, the lipophilic p-chloro group is very important for the antiviral activity. Again, compound (16) containing both 2- and 3-OH groups showed a higher cytotoxic activity compared to compound (15) with only 3-OH group as mentioned before.
- (d)
- The presence of the acetyl methylene group at positions 2 and/or 3 in compounds (5, 7, and 6) gave better cytotoxic activities compared to the heteroaromatic ring substitutions at the same positions in compounds (12, 14, and 13).
- (e)
- The cytotoxic activity of compound (17) containing the isoxazole side chain with a p-chlorophenyl substitution (IC50 = 4.12 µM) was clearly higher than the respective same compound (10) with a phenyl triazole side chain instead (IC50 = 75.31 µM).
2.2.5. Mechanism of Actions
3. Materials and Methods
3.1. Chemistry
3.1.1. Green Chemistry Condition for Extraction and Purification of OA (1) and MA (2) from the Pomace Olive of Olea europaea L.
3.1.2. Synthesis
Multicomponent Synthesis of 1,5-Disubstituted Triazoles in Water Catalyzed by Cp*RuCl (PPh3)2
Cu(I))-Cuatalyzed Multicomponent Huisgen 1,3-Dipolar Cycloaddition Reaction
Multicomponent Synthesis of 3,5-Disubstituted Isoxazoles in Water Catalyzed by CuI
3.2. Biological
3.2.1. Molecular Docking Studies
3.2.2. Preparation of the Selected Tested Compounds
3.2.3. Preparation of the Active Site of the Applied SARS-CoV-2 Mpro Receptor
3.2.4. Validation of the Applied MOE Program
3.2.5. Docking of the Prepared Database to the Binding Pocket of SARS-CoV-2 Mpro Receptor
3.2.6. In Vitro Antiviral Bioassay
Cytotoxicity (CC50) Determination
Inhibitory Concentration 50 (IC50) Determination
Mechanism of Action(s) for Compound 17
- (a)
- Viral adsorption mechanism
- (b)
- Viral replication mechanism
- (c)
- Virucidal mechanism
4. Conclusions
5. Patents
Supplementary Materials
Author Contributions
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Cultivar | Extraction Methods | Yield of Extraction (mg/g DW) | References | |
---|---|---|---|---|
Oleanolic Acid 1 | Maslinic Acid 2 | |||
Picual | Solid–liquid extraction (maceration) | 0.500 | 1.200 | [41] |
Hojiblanca | 0.500 | 1.300 | ||
Arbequina | 0.400 | 1.500 | ||
Non-indicated | 0.015 | 0.034 | [42] | |
Manzanilla | Solid–liquid extraction (centrifugation) | 0.274 | 0.824 | [43] |
Hojiblanca | 0.565 | 0.904 | ||
Cacereña | 0.185 | 0.295 | ||
Kalamata | 0.841 | 1.318 | ||
Picual | Ultrasonic-assisted extraction | 1.003 | 2.440 | [44] |
Kalamon | 0.838 | 2.100 | ||
Chemlali | Solid–liquid, then ultrasonic-assisted extractions | 3.400 | 8.500 | [15] |
Chemlali | Ultrasonic-assisted extractions, then centrifugation isolation | 3.6 | 9.2 | This work |
Code | Nomenclature | Chemical Structures | Yield (%) |
---|---|---|---|
1 | Oleanolic acid | - | |
2 | Maslinic acid | - | |
3 | Propargyl-(3β)-3-hydroxyolean-12-en-28-oate | 99 | |
4 | Propargyl-(2α,3β)-2,3-dihydroxyolean-12-en-28-oate | 25 | |
5 | Propargyl-(2α)-2-(propargyloxy)-(3β)-3-hydroxy-olean-12-en-28-oate | 23 | |
6 | Propargyl-(3α)-3-(propargyloxy)-(2β)-2-hydroxy-olean-12-en-28-oate | 20 | |
7 | Propargyl-(2α,3β)-2,3-bis(propargyloxy)-olean-12-en-28-oate | 31 | |
8 | (1-(3-methylphenyl)-1H-1,2,3-triazol-5-yl)methyl-(3β)-3-hydroxyolean-12-en-28-oate | 90 | |
9 | (1-(3-methylphenyl)-1H-1,2,3-triazol-5-yl)methyl-(2α,3β)-2,3-dihydroxyolean-12-en-28-oate | 92 | |
10 | (1-(3-methylphenyl)-1H-1,2,3-triazol-4-yl)methyl-(3β)-3-hydroxyolean-12-en-28-oate | 98 | |
11 | (1-Phenyl-1H-1,2,3-triazol-4-yl)methyl-(2α,3β)-2,3-dihydroxyolean-12-en-28-oate | 96 | |
12 | (1-(4-Chlorophenyl)-1H-1,2,3-triazol-4-yl)methyl-(2α,3β)-2-((1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)-3-hydroxyolean-12-en-28-oate | 94 | |
13 | (1-(4-Methoxyphenyl)-1H-1,2,3-triazol-4-yl)methyl-(2α,3β)-2-hydroxy-3-((1-(4-methoxyphenyl)-1H-1,2,3-triazol-4-yl)methoxy)-olean-12-en-28-oate | 96 | |
14 | (1-(4-Methoxyphenyl)-1H-1,2,3-triazol-4-yl)methyl-(2α,3β)-2,3-bis((1-(4-methoxyphenyl)-1H-1,2,3-triazol-4-yl)methoxy)-olean-12-en-28-oate | 92 | |
15 | (3-(4-methoxyphenyl) isoxazol-5-yl) methyl-(3β)-3-hydroxyolean-12-en-28-oate | 98 | |
16 | (3-(4-methoxyphenyl) isoxazol-5-yl) methyl-(2α,3β)-2,3-dihydroxyolean-12-en-28-oate | 87 | |
17 | (3-(4-chlorophenyl) isoxazol-5-yl) methyl-(2α,3β)-2,3-dihydroxyolean-12-en-28-oate | 96 | |
18 | N3 (co-crystallized native inhibitor of SARS-CoV-2) | - |
Code | 3D Binding Interactions | 3D Pocket Positioning |
---|---|---|
17 | ||
3 | ||
N3 (18) |
Compound | CC50 | IC50 | Selectivity Index (CC50/IC50) |
---|---|---|---|
1 | 189.9 | 476.1 | 0.39 |
2 | 97.30 | 99.87 | 0.97 |
3 | 97.40 | 42.01 | 2.32 |
4 | 157.2 | 236.3 | 0.67 |
5 | 90.62 | 85.21 | 1.06 |
6 | 208.8 | 135 | 1.55 |
7 | 97.42 | 108 | 0.90 |
8 | 170 | 173.9 | 0.98 |
9 | 185.3 | 131.9 | 1.40 |
10 | 277.2 | 75.31 | 3.68 |
11 | 218.1 | 134.7 | 1.62 |
12 | 513.8 | 116.1 | 4.42 |
13 | 356.4 | 158.9 | 2.24 |
14 | 405.4 | 136.7 | 2.96 |
15 | 415.3 | 523 | 0.79 |
16 | 324.2 | 218.6 | 1.48 |
17 | 141.6 | 4.12 | 34.36 |
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Soltane, R.; Chrouda, A.; Mostafa, A.; Al-Karmalawy, A.A.; Chouaïb, K.; dhahri, A.; Pashameah, R.A.; Alasiri, A.; Kutkat, O.; Shehata, M.; et al. Strong Inhibitory Activity and Action Modes of Synthetic Maslinic Acid Derivative on Highly Pathogenic Coronaviruses: COVID-19 Drug Candidate. Pathogens 2021, 10, 623. https://doi.org/10.3390/pathogens10050623
Soltane R, Chrouda A, Mostafa A, Al-Karmalawy AA, Chouaïb K, dhahri A, Pashameah RA, Alasiri A, Kutkat O, Shehata M, et al. Strong Inhibitory Activity and Action Modes of Synthetic Maslinic Acid Derivative on Highly Pathogenic Coronaviruses: COVID-19 Drug Candidate. Pathogens. 2021; 10(5):623. https://doi.org/10.3390/pathogens10050623
Chicago/Turabian StyleSoltane, Raya, Amani Chrouda, Ahmed Mostafa, Ahmed A. Al-Karmalawy, Karim Chouaïb, Abdelwaheb dhahri, Rami Adel Pashameah, Ahlam Alasiri, Omnia Kutkat, Mahmoud Shehata, and et al. 2021. "Strong Inhibitory Activity and Action Modes of Synthetic Maslinic Acid Derivative on Highly Pathogenic Coronaviruses: COVID-19 Drug Candidate" Pathogens 10, no. 5: 623. https://doi.org/10.3390/pathogens10050623