Galantamine-Curcumin Hybrids as Dual-Site Binding Acetylcholinesterase Inhibitors
Abstract
:1. Introduction
2. Results
2.1. Design of GAL-CU Hybrids
2.2. ADME Filters
2.3. Virtual Screening by Molecular Docking
2.4. GAL-CU Hybrids Selected for Synthesis
2.5. Synthesis of Selected GAL-CU Hybrids
2.5.1. Synthesis of Hybrids 4a–c,e–h
2.5.2. Synthesis of Hybrids 6a and 6b
2.5.3. Synthesis of Hybrids 8b,c,f,g,h
2.6. Neurotoxicity of the GAL-CU Hybrids
2.7. Anti-AChE Activity
2.8. Physicochemical Properties and PK Parameters
2.9. Molecular Dynamics Simulation of the Complex 4b-AChE
3. Discussion
4. Materials and Methods
4.1. Compounds
4.2. ADME Prediction
4.3. Virtual Screening by Molecular Docking
4.4. Neurotoxicity Test
4.5. Assessment of AChE Inhibitory Activity
4.6. Calculation of Physicochemical Properties and Prediction of Pharmacokinetic (PK) Parameters
4.7. Molecular Dynamics Protocol
Supplementary Materials
Author Contributions
Funding
Conflicts of Interest
References
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Sample Availability: Samples of the compounds 4a–c,e–h, 6a,b, 8b,c,f,g,h are available from the authors. |
ID | GoldScore | IC50 µM Neuro-2A | IC50 µM eeAChE | Times More Active Than GAL |
---|---|---|---|---|
8c | 114.54 | 25.55 | - | - |
6a | 114.50 | 12.14 | - | - |
8g | 111.92 | 17.80 | - | - |
6b | 111.15 | 7.91 | - | - |
8f | 109.22 | 24.32 | - | - |
8h | 108.95 | 25.00 | - | - |
8b | 104.01 | 28.87 | 0.086 | 41 |
4h | 96.98 | 21.93 | - | - |
4e | 96.07 | 42.91 | 0.036 | 98 |
4f | 95.05 | 34.35 | 0.033 | 110 |
4b | 94.31 | 52.53 | 0.020 | 186 |
4a | 93.74 | 30.65 | 0.046 | 75 |
4g | 90.71 | 23.68 | - | - |
4c | 88.28 | 24.11 | - | - |
GAL | 74.56 a | >50 a | 3.520 | 1 |
CU | 88.93 | 26.30 | 67.69 b |
Parameter | 4a | 4b | 4e | 4f | 8b | GAL |
---|---|---|---|---|---|---|
Mw | 459.58 | 489.60 | 503.59 | 473.60 | 523.62 | 287.35 |
pKa | 7.78 | 7.77 | 7.77 | 7.77 | 6.58 | 7.92 |
logP | 4.53 ± 0.8 | 4.48 ± 0.81 | 4.64 ± 0.85 | 4.99 ± 0.80 | 4.9 ± 0.85 | 1.75 |
logD7.4 | 3.97 | 3.92 | 4.09 | 4.43 | 4.83 | 1.12 |
PSA | 59.00 | 68.23 | 77.46 | 59.00 | 68.23 | 41.93 |
HBD | 1 | 1 | 1 | 1 | 1 | 1 |
HBA | 5 | 6 | 7 | 5 | 6 | 4 |
fBH+ | 0.71 | 0.70 | 0.70 | 0.70 | 0.13 | 0.77 |
VDssL/kg | 4.71 | 4.95 | 5.88 | 5.31 | 1.85 | 2.30 a |
fu | 0.082 | 0.085 | 0.094 | 0.078 | 0.029 | 0.83 a |
CL, L/h/kg | 0.466 | 0.412 | 0.388 | 0.445 | 0.305 | 0.336 a |
t1/2, h | 7.01 | 8.32 | 10.51 | 8.28 | 4.19 | 4.74 |
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Stavrakov, G.; Philipova, I.; Lukarski, A.; Atanasova, M.; Zheleva, D.; Zhivkova, Z.D.; Ivanov, S.; Atanasova, T.; Konstantinov, S.; Doytchinova, I. Galantamine-Curcumin Hybrids as Dual-Site Binding Acetylcholinesterase Inhibitors. Molecules 2020, 25, 3341. https://doi.org/10.3390/molecules25153341
Stavrakov G, Philipova I, Lukarski A, Atanasova M, Zheleva D, Zhivkova ZD, Ivanov S, Atanasova T, Konstantinov S, Doytchinova I. Galantamine-Curcumin Hybrids as Dual-Site Binding Acetylcholinesterase Inhibitors. Molecules. 2020; 25(15):3341. https://doi.org/10.3390/molecules25153341
Chicago/Turabian StyleStavrakov, Georgi, Irena Philipova, Atanas Lukarski, Mariyana Atanasova, Dimitrina Zheleva, Zvetanka D. Zhivkova, Stefan Ivanov, Teodora Atanasova, Spiro Konstantinov, and Irini Doytchinova. 2020. "Galantamine-Curcumin Hybrids as Dual-Site Binding Acetylcholinesterase Inhibitors" Molecules 25, no. 15: 3341. https://doi.org/10.3390/molecules25153341