New Cysteine Protease Inhibitors: Electrophilic (Het)arenes and Unexpected Prodrug Identification for the Trypanosoma Protease Rhodesain
Abstract
:1. Introduction
2. Results
2.1. Syntheses
2.2. Enzyme Assays
2.3. 19F NMR Spectroscopy
2.4. Mass Spectrometry
2.5. Hydrolysis of Ester 7 by Rhodesain
2.6. Reaction of Inhibitor 7 with a Low Molecular Weight Thiol
2.7. Theoretical Investigations of the Enzyme-Inhibitor Complex
2.8. T. b. brucei Cell Survival Assay
3. Discussion
4. Materials and Methods
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Sample Availability: Samples of the compounds are available from the authors. |
Cpd. | Cath. L | Cath. B | Rhod. | DENV PR | Sortase A |
---|---|---|---|---|---|
% inh./Ki | % inh./Ki | % inh./Ki | % inh./Ki | % inh./Ki | |
1 | 57/nd | 16/nd | nd/nd | 19/nd | nd/nd |
2 | 56/nd | 33/nd | nd/nd | 24/nd | nd/nd |
3 | 60/nd | 22/nd | nd/nd | 28/nd | nd/nd |
4 | 99/0.66 | 20/nd | 75/0.29 | 10/nd | 11/nd |
5 | 8/nd | 10/nd | nd/nd | 11/nd | nd/nd |
6 | 50/nd | 21/nd | nd/nd | 12/nd | nd/nd |
7 | 98/1.6 | 63/4.4 | 45/nd | 31/nd | 16/nd |
Structure | ωB97XD | MP2 | SCS-MP2 |
---|---|---|---|
Pre-complex | –8.8/–9.0/ | –12.3/–16.0/- | –10.3/–12.8/ |
S-CH | +0.8/–11.5/–6.8 | –6.6/–16.0/–12.8 | –4.1/–12.9/–9.3 |
S-CF | –3.3/–13.1/–3.1 | –13.2/–20.3/–12.5 | –11.1/–16.5/–10.1 |
S-NO2 | –2.7/–9.3/+3.3 | –11.9/–17.0/–5.3 | –9.1/–13.3/–2.9 |
Starting Structure | R(S-CNO2) | R(S-CH) | ΔE |
---|---|---|---|
MD 6 Frame 963 conformer with short Cys-S…H-N distance | 3.7 | 0.0 | |
3.3 | 1.4 | ||
3.1 | 1.7 | ||
2.9 | 2.5 | ||
MD 6 Frame 1096 conformer with short Cys-S…H-N distance | 3.7 | 0.0 | |
3.3 | 0.7 | ||
3.1 | 0.8 | ||
2.9 | 2.6 | ||
MD 6 Frame 542 conformer with short Cys-S…H-N distance | 4.9 | 0.0 | |
4.5 | 1.2 | ||
4.1 | 3.4 | ||
3.9 | 0.4 | ||
3.5 | 5.3 |
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Klein, P.; Johe, P.; Wagner, A.; Jung, S.; Kühlborn, J.; Barthels, F.; Tenzer, S.; Distler, U.; Waigel, W.; Engels, B.; Hellmich, U.A.; Opatz, T.; Schirmeister, T. New Cysteine Protease Inhibitors: Electrophilic (Het)arenes and Unexpected Prodrug Identification for the Trypanosoma Protease Rhodesain. Molecules 2020, 25, 1451. https://doi.org/10.3390/molecules25061451
Klein P, Johe P, Wagner A, Jung S, Kühlborn J, Barthels F, Tenzer S, Distler U, Waigel W, Engels B, Hellmich UA, Opatz T, Schirmeister T. New Cysteine Protease Inhibitors: Electrophilic (Het)arenes and Unexpected Prodrug Identification for the Trypanosoma Protease Rhodesain. Molecules. 2020; 25(6):1451. https://doi.org/10.3390/molecules25061451
Chicago/Turabian StyleKlein, Philipp, Patrick Johe, Annika Wagner, Sascha Jung, Jonas Kühlborn, Fabian Barthels, Stefan Tenzer, Ute Distler, Waldemar Waigel, Bernd Engels, Ute A. Hellmich, Till Opatz, and Tanja Schirmeister. 2020. "New Cysteine Protease Inhibitors: Electrophilic (Het)arenes and Unexpected Prodrug Identification for the Trypanosoma Protease Rhodesain" Molecules 25, no. 6: 1451. https://doi.org/10.3390/molecules25061451