Novel Sulfonamide-Based Carbamates as Selective Inhibitors of BChE
Abstract
:1. Introduction
2. Results and Discussion
2.1. Chemistry
2.2. In Vitro Evaluation of AChE- and BChE-Inhibiting Activity
2.3. Evaluation of Carbamylation and Reactivation of BChE
2.4. Molecular Modeling Studies
QTAIM Calculations
2.5. Cytotoxicity Evaluation and ADME Predictions
3. Materials and Methods
3.1. General
3.2. Chemistry
3.2.1. General Experimental Procedure for the Synthesis of N-Cbz Alcohols 2a–c
3.2.2. General Experimental Procedure for the Synthesis of Mesylates 3a–c
3.2.3. General Experimental Procedure for the Synthesis of Thioacetates 4a–c
3.2.4. General Experimental Procedure for the Synthesis of the Investigated Sulfonates 5a–5n
3.3. AChE and BChE Inhibition Studies
3.4. Kinetic Studies
3.5. Molecular Modeling
3.5.1. Receptor Preparation and Docking Procedure
3.5.2. Molecular Dynamic Simulations
3.5.3. MM-GBSA Free Energy Decomposition
3.5.4. QTAIM Analysis
3.6. Cytotoxicity Evaluation
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Comp. | Structure | IC50 (µM) | SI * | |
---|---|---|---|---|
AChE | BChE | |||
5a | 90.56 ± 5.70 | 100.25 ± 4.26 | 0.90 | |
5b | 76.95 ± 1.52 | 86.12 ± 1.91 | 0.89 | |
5c | 91.81 ± 4.89 | 8.52 ± 0.32 | 10.78 | |
5d | 55.64 ± 1.38 | 16.54 ± 0.10 | 3.36 | |
5e | 108.46 ± 2.39 | 58.94 ± 1.88 | 1.84 | |
5f | 114.73 ± 6.22 | 15.29 ± 0.38 | 7.50 | |
5g | 78.83 ± 0.63 | 12.61 ± 0.31 | 6.25 | |
5h | 61.39 ± 0.47 | 11.54 ± 0.28 | 5.32 | |
5i | 61.65 ± 1.47 | 112.21 ± 3.41 | 0.55 | |
5j | 67.47 ± 0.37 | 6.57 ± 0.12 | 10.27 | |
5k | 150.29 ± 3.82 | 4.33 ± 0.07 | 34.71 | |
5l | 92.91 ± 2.47 | 55.64 ± 1.38 | 1.67 | |
5m | 131.85 ± 0.42 | 19.99 ± 0.17 | 5.70 | |
5n | 95.14 ± 2.77 | 13.51 ± 0.51 | 7.04 | |
RIV | – | 56.10 ± 1.41 | 38.40 ± 1.97 | 1.46 |
Comp. | R | MW | logP | HBD | HBA | RB | TPSA | HJS (cm/s) | ka (min−1) | logKaHSA | %PPB | logPS | logBB |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
5c | 404.52 | 3.69 | 2 | 6 | 11 | 92.88 | 7.22 × 10−4 | 0.050 | 5.18 | 90.52 | −1.3 | 0.49 | |
5f | 418.55 | 4.04 | 2 | 6 | 12 | 92.88 | 7.13 × 10−4 | 0.049 | 5.22 | 91.70 | −1.3 | 0.63 | |
5j | 438.97 | 4.68 | 2 | 6 | 11 | 92.88 | 7.15 × 10−4 | 0.0449 | 5.34 | 94.64 | −1.2 | 0.74 | |
5k | 434.55 | 3.95 | 2 | 7 | 12 | 102.11 | 7.09 × 10−4 | 0.049 | 5.20 | 89.60 | −1.3 | 0.68 | |
5n | 459.39 | 5.17 | 2 | 6 | 10 | 92.88 | 7.17 × 10−4 | 0.049 | 5.68 | 96.90 | −1.8 | 0.42 | |
rivastigmine | 250.34 | 2.29 | 0 | 4 | 5 | 32.78 | 6.89 × 10−4 | 0.047 | 3.57 | 33.55 | −1.9 | 0.51 | |
galantamine | 287.35 | 1.55 | 1 | 4 | 1 | 41.93 | 4.37 × 10−4 | 0.030 | 3.38 | 19.99 | −2.2 | 0.28 | |
Ro5 | <500 | <5 | <5 | <10 | – | – | – | – | – | – | – | – |
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Magar, P.; Parravicini, O.; Štěpánková, Š.; Svrčková, K.; Garro, A.D.; Jendrzejewska, I.; Pauk, K.; Hošek, J.; Jampílek, J.; Enriz, R.D.; et al. Novel Sulfonamide-Based Carbamates as Selective Inhibitors of BChE. Int. J. Mol. Sci. 2021, 22, 9447. https://doi.org/10.3390/ijms22179447
Magar P, Parravicini O, Štěpánková Š, Svrčková K, Garro AD, Jendrzejewska I, Pauk K, Hošek J, Jampílek J, Enriz RD, et al. Novel Sulfonamide-Based Carbamates as Selective Inhibitors of BChE. International Journal of Molecular Sciences. 2021; 22(17):9447. https://doi.org/10.3390/ijms22179447
Chicago/Turabian StyleMagar, Pratibha, Oscar Parravicini, Šárka Štěpánková, Katarina Svrčková, Adriana D. Garro, Izabela Jendrzejewska, Karel Pauk, Jan Hošek, Josef Jampílek, Ricardo D. Enriz, and et al. 2021. "Novel Sulfonamide-Based Carbamates as Selective Inhibitors of BChE" International Journal of Molecular Sciences 22, no. 17: 9447. https://doi.org/10.3390/ijms22179447