Design, Synthesis and Evaluation of Fused Bicyclo[2.2.2]octene as a Potential Core Scaffold for the Non-Covalent Inhibitors of SARS-CoV-2 3CLpro Main Protease
Abstract
:1. Introduction
2. Results and Discussion
2.1. Structure-Based Design of Fused Bicyclo[2.2.2]octene as a Core Scaffold of SARS-CoV-2 3CLpro Inhibitors
2.2. Synthesis of Fused Bicyclo[2.2.2]octenes
2.3. Inhibition of SARS-CoV-2 3CLpro Main Protease
2.4. Computational Evaluation of Inhibitor Binding to 3CLpro
3. Materials and Methods
3.1. Synthetic Procedures and Compounds Characterization Data
3.2. FRET-Based Assay of SARS-CoV-2 3CLpro Main Protease Inhibition Activity
3.3. Molecular Docking Calculations and Binding Site Analysis Using Molecular Probes
3.4. Molecular Dynamics Simulations
Analysis of the MD Trajectories
- (a)
- Cα RMSD and RMSF calculations
- (b)
- MM/GBSA binding free energy calculations
- (c)
- Dynamic pharmacophore model calculations
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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Entry | Starting Bicyclo[2.2.2]octenes 9 | Hydrazide 10 | n(10) in mmol | Product 11 | Yield (%) b | |||
---|---|---|---|---|---|---|---|---|
R1 | R2 | R3 | ||||||
1 | H | H | Ph | 9a | 10a | 2.0 | 11a | 69 |
2 | H | H | Ph | 9a | 10b | 2.0 | 11b | 70 |
3 | H | H | Ph | 9a | 10c | 2.0 | 11c | 72 |
4 | Me | H | Ph | 9b | 10a | 2.0 | 11d c | 62 |
5 | Me | H | Ph | 9b | 10b | 2.0 | 11e c | 84 |
6 | H | H | 2-thienyl | 9c | 10a | 1.5 | 11f | 72 |
7 | H | H | 2-thienyl | 9c | 10b | 1.5 | 11g | 79 |
8 | H | H | 2-thienyl | 9c | 10c | 1.5 | 11h | 77 |
9 | H | H | 2-furyl | 9d | 10a | 1.5 | 11i | 68 |
10 | H | H | 2-furyl | 9d | 10b | 1.5 | 11j | 70 |
11 | H | H | 2-furyl | 9d | 10c | 1.5 | 11k | 73 |
12 | H | 4-MeO-C6H4- | Me | 9e | 10a | 1.1 | 11l | 64 |
13 | H | 4-MeO-C6H4- | Me | 9e | 10b | 1.1 | 11m | 67 |
14 | H | 4-MeO-C6H4- | Me | 9e | 10c | 1.1 | 11n | 64 |
15 | H | COMe | Me | 9f | 10b | 1.65 | 11o d | 48 |
R1 | R2 | R3 | IC50 [μM] | |
11a | H | H | Ph | 102.2 |
11d | Me | H | Ph | <1000 |
11f | H | H | 2-thienyl | <1000 |
11i | H | H | 2-furyl | <1000 |
11l | H | 4-MeO-C6H4- | Me | <1000 |
R1 | R2 | R3 | ||
11b | H | H | Ph | <1000 |
11e | Me | H | Ph | ~200.0 |
11g | H | H | 2-thienyl | <1000 |
11j | H | H | 2-furyl | <1000 |
11m | H | 4-MeO-C6H4- | Me | <1000 |
11o | H | -C(Me)=NNH-CO-(3-pyridyl) | Me | <1000 |
R1 | R2 | R3 | ||
11c | H | H | Ph | <1000 |
11h | H | H | 2-thienyl | <1000 |
11k | H | H | 2-furyl | <1000 |
11n | H | 4-MeO-C6H4- | Me | <1000 |
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Herlah, B.; Hoivik, A.; Jamšek, L.; Valjavec, K.; Yamamoto, N.; Hoshino, T.; Kranjc, K.; Perdih, A. Design, Synthesis and Evaluation of Fused Bicyclo[2.2.2]octene as a Potential Core Scaffold for the Non-Covalent Inhibitors of SARS-CoV-2 3CLpro Main Protease. Pharmaceuticals 2022, 15, 539. https://doi.org/10.3390/ph15050539
Herlah B, Hoivik A, Jamšek L, Valjavec K, Yamamoto N, Hoshino T, Kranjc K, Perdih A. Design, Synthesis and Evaluation of Fused Bicyclo[2.2.2]octene as a Potential Core Scaffold for the Non-Covalent Inhibitors of SARS-CoV-2 3CLpro Main Protease. Pharmaceuticals. 2022; 15(5):539. https://doi.org/10.3390/ph15050539
Chicago/Turabian StyleHerlah, Barbara, Andrej Hoivik, Luka Jamšek, Katja Valjavec, Norio Yamamoto, Tyuji Hoshino, Krištof Kranjc, and Andrej Perdih. 2022. "Design, Synthesis and Evaluation of Fused Bicyclo[2.2.2]octene as a Potential Core Scaffold for the Non-Covalent Inhibitors of SARS-CoV-2 3CLpro Main Protease" Pharmaceuticals 15, no. 5: 539. https://doi.org/10.3390/ph15050539