Targeting Alzheimer’s Disease: Evaluating the Efficacy of C-1 Functionalized N-Aryl-Tetrahydroisoquinolines as Cholinergic Enzyme Inhibitors and Promising Therapeutic Candidates
Abstract
:1. Introduction
2. Results and Discussion
2.1. Chemistry—Synthesis of Compounds
2.2. Evaluation of the Cholinesterase’ Enzymes Inhibition Potency and SAR Discussion
2.3. Kinetic Studies of Enzymes Inhibition
2.4. Influence of Inhibitors Binding on the Trp−AChE/BuChE Fluorescence
2.5. Docking Studies
2.6. ADME Prediction, log P, and the Blood−Brain Barrier Permeability Determination
2.6.1. In Silico ADME Predictions for Selected THIQs
2.6.2. Ultra-High-Performance Chromatography log P Determination and the In Vitro BBB Permeability Study
Compound | logP | PAMPA-BBB Permeability Pe; 10−6 cm s−1 |
---|---|---|
3c | 3.39 | 47.5 |
3f | 3.66 | High hydrophobicity; it retained in the membrane |
3i | 3.78 | High hydrophobicity; it retained in the membrane |
Verapamil × HCl | 3.80 [32] | 15.8 |
Caffeine | −0.07 [33] | 1.47 |
3. Conclusions
4. Experimental Section
4.1. Chemicals
4.2. In Vitro Inhibitory Evaluation on AChE/BChE
4.3. Kinetics Studies of ChE’s Inhibition
4.4. Fluorescence Measurements
4.5. In Silico Prediction of ADME
4.6. Determination of Partition Coefficient (logP) of Tested Compounds by UPLC Methods
4.7. PAMPA-BBB Permeability Assay
4.8. Quantum-Mechanical Calculations
4.9. Molecular Docking
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Compound | Structure | Residual Activity at 1 × 10−5 M | IC50, μM | Selectivity Index for AChE a | ||
---|---|---|---|---|---|---|
AChE | BuChE | AChE | BuChE | |||
1a | n.a. | 11 | >10 | >10 | - | |
2a | 30 | 43 | >10 | >10 | - | |
2b | 64 | 47 | 5.46 ± 0.58 | 8.90 ± 2.03 | 1.63 | |
2c | 68 | 2 | 5.04 ± 0.28 | >10 | - | |
2d | 12 | 15 | >10 | >10 | - | |
2e | 20 | n.a. | >10 | n.d. | - | |
2f | n.a. | n.a. | n.d. | n.d. | - | |
3a | 100 | 54 | 4.29 ± 0.09 | 8.26 ± 1.05 | 1.93 | |
3b | 59 | 20 | 9.05 ± 0.81 | >10 | - | |
3c | 100 | 37 | 1.95 ± 0.23 | >10 | >5 | |
3d | 70 | 20 | 4.89 ± 0.15 | >10 | - | |
3e | 45 | n.a. | >10 | n.d. | - | |
3f | 100 | 75 | 2.42 ± 0.09 | 6.28 ± 0.36 | 2.59 | |
3g | 75 | 30 | 6.78 ± 0.22 | 8.01 ± 0.55 | 1.18 | |
3h | 40 | 10 | >10 | >10 | - | |
3i | 100 | 100 | 1.11 ± 0.04 | 2.72 ± 0.20 | 2.45 | |
3j | 100 | 100 | 2.91 ± 0.09 | 4.52 ± 0.15 | 1.55 | |
3k | 70 | 30 | 4.02 ± 0.19 | >10 | - | |
3l | 45 | 5 | >10 | >10 | - | |
4a | 12 | 23 | >10 | >10 | - | |
4b | 20 | 20 | >10 | >10 | - | |
4c | 18 | 30 | >10 | >10 | - | |
Tacrine | - | - | - | 0.06 ± 0.001 | 0.008 ± 0.001 | 0.13 |
Donepezil | - | - | - | 0.02 ± 0.001 | 3.67 ± 0.05 | 183 |
Enzyme | Inhibitor | IC50, μM | Ki, μM | Type of Inhibition |
---|---|---|---|---|
AChE | 3c | 1.91 ± 0.11 | 1.78 ± 0.10 | Non-competitive |
3i | 1.11 ± 0.04 | 1.06 ± 0.01 | Non-competitive | |
BuChE | 3c | n.a. | / | / |
3i | 2.71 ± 0.20 | 1.04 ± 0.1 | Mix non-competitive/uncompetitive |
Ksv, M−1 | kq, M−1s−1 | Ka, M | n | |
---|---|---|---|---|
3i | (6.96 ± 0.05) × 104 | (6.96 ± 0.05) × 1014 | (3.31 ± 0.05) × 104 | 0.94 ± 0.04 |
Label of Compounds | AChE | BuChE | ||||
---|---|---|---|---|---|---|
Conf | ΔE | No | Conf | ΔE | No | |
3c | R | −9.2 | 1 | R | −7.9 | / |
S | −8.9 | 1 | S | −7.5 | / | |
3i | R | −9.9 | 1 | R | −8.7 | 1 |
S | −9.2 | 1 | S | −8.2 | 1 |
Compounds | |||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Parameters | 2b | 2c | 3a | 3b | 3c | 3d | 3f * | 3g | 3i * | 3j * | 3k | Tacrine | Donepezil |
Mw, g/mol | 283.3 | 325.4 | 327.4 | 357.4 | 387.5 | 405.5 | 341.5 | 401.5 | 369.5 | 387.5 | 429.6 | 198.3 | 379.5 |
TPSA, Å2 | 20.3 | 38.8 | 20.3 | 29.5 | 38.8 | 38.8 | 20.3 | 38.8 | 20.3 | 20.3 | 38.8 | 38.9 | 38.8 |
ClogP | 3.45 | 3.09 | 4.25 | 4.21 | 4.16 | 4.48 | 4.57 | 4.46 | 5.00 | 5.26 | 4.90 | 2.59 | 4.00 |
ilogP | 2.58 | 2.89 | 3.09 | 3.29 | 3.38 | 3.50 | 3.36 | 3.51 | 3.76 | 3.61 | 3.99 | 2.09 | 3.92 |
MlogP | 3.58 | 2.46 | 4.08 | 3.68 | 3.31 | 3.68 | 4.30 | 3.51 | 4.71 | 5.08 | 3.91 | 2.33 | 3.06 |
XlogP | 3.36 | 3.21 | 4.92 | 4.89 | 4.86 | 4.96 | 5.28 | 5.22 | 5.51 | 5.61 | 5.45 | 2.71 | 4.28 |
WlogP | 3.62 | 3.08 | 4.36 | 4.37 | 4.38 | 4.93 | 4.75 | 4.77 | 5.07 | 5.63 | 5.08 | 2.70 | 3.83 |
logS (ESOL) | −3.94 | −3.92 | −5.24 | −5.30 | −5.37 | −5.53 | −5.47 | −5.60 | −5.62 | −5.77 | −5.76 | −3.27 | −4.81 |
No. H-bond acceptor | 2 | 3 | 1 | 2 | 3 | 4 | 1 | 3 | 1 | 2 | 3 | 1 | 4 |
No. H-bond donor | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 |
No. rotable bonds | 3 | 5 | 4 | 5 | 6 | 6 | 5 | 7 | 7 | 7 | 9 | 0 | 6 |
BBB permeation | yes | yes | yes | yes | yes | yes | yes | yes | yes | yes | yes | yes | yes |
LogKP (skin permeation), cm/s | −5.64 | −6.01 | −4.80 | −5.01 | −5.21 | −5.25 | −4.63 | −5.04 | −4.64 | −4.68 | −5.05 | −5.59 | −5.58 |
Lipinski’s rule violations | no | no | no | no | no | no | yes | no | yes | yes | no | no | no |
Bioavailability score | 0.55 | 0.55 | 0.55 | 0.55 | 0.55 | 0.55 | 0.55 | 0.55 | 0.55 | 0.55 | 0.55 | 0.55 | 0.55 |
GI absorbtion | high | high | high | high | high | high | high | high | high | high | high | high | high |
PAINS alerts | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
P-pg substrate | yes | yes | yes | yes | yes | yes | yes | yes | yes | yes | yes | yes | yes |
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Jovanović, D.; Filipović, A.; Janjić, G.; Lazarević-Pašti, T.; Džambaski, Z.; Bondžić, B.P.; Bondžić, A.M. Targeting Alzheimer’s Disease: Evaluating the Efficacy of C-1 Functionalized N-Aryl-Tetrahydroisoquinolines as Cholinergic Enzyme Inhibitors and Promising Therapeutic Candidates. Int. J. Mol. Sci. 2024, 25, 1033. https://doi.org/10.3390/ijms25021033
Jovanović D, Filipović A, Janjić G, Lazarević-Pašti T, Džambaski Z, Bondžić BP, Bondžić AM. Targeting Alzheimer’s Disease: Evaluating the Efficacy of C-1 Functionalized N-Aryl-Tetrahydroisoquinolines as Cholinergic Enzyme Inhibitors and Promising Therapeutic Candidates. International Journal of Molecular Sciences. 2024; 25(2):1033. https://doi.org/10.3390/ijms25021033
Chicago/Turabian StyleJovanović, Dunja, Ana Filipović, Goran Janjić, Tamara Lazarević-Pašti, Zdravko Džambaski, Bojan P. Bondžić, and Aleksandra M. Bondžić. 2024. "Targeting Alzheimer’s Disease: Evaluating the Efficacy of C-1 Functionalized N-Aryl-Tetrahydroisoquinolines as Cholinergic Enzyme Inhibitors and Promising Therapeutic Candidates" International Journal of Molecular Sciences 25, no. 2: 1033. https://doi.org/10.3390/ijms25021033