Design, Synthesis, and Biological Evaluation of Pyridazinones Containing the (2-Fluorophenyl) Piperazine Moiety as Selective MAO-B Inhibitors
Abstract
:1. Introduction
2. Results and Discussion
2.1. Chemistry
2.2. MAO Inhibitory Activities
2.3. Kinetics of MAO-B Inhibitions
2.4. Reversibility Studies
2.5. Cytotoxic Effects of the Active Pyridazinone Derivatives
2.6. Molecular Docking Studies
2.7. ADME Prediction
3. Materials and Methods
3.1. Chemical Studies
3.2. Synthesis of Intermediates
3.2.1. Synthesis of 3-chloro-6-[4-(2-fluorophenyl)piperazine-1-yl]pyridazine (1)
3.2.2. Synthesis of 6-(4-(2-fluorophenyl)piperazine-1-yl)-3(2H)-pyridazinone (2)
3.2.3. Synthesis of ethyl 6-(4-(2-fluorophenyl)piperazine-1-yl)-3(2H)-pyridazinone-2-yl-acetate (3)
3.2.4. Synthesis of 6-(4-(2-fluorophenyl)piperazine-1-yl)-3(2H)-pyridazinone-2-yl-acetohydrazide (4)
3.2.5. General Procedure for the Synthesis of T1–T12
3.2.6. 6-[4-(2-Fluorophenyl)piperazine-1-yl]-3(2H)-pyridazinone-2-acetyl-2-(3-bromobenzal)hydrazon (T8)
3.2.7. 6-[4-(2-Fluorophenyl)piperazine-1-yl]-3(2H)-pyridazinone-2-acetyl-2-(2-fluorobenzal)hydrazon (T9)
3.2.8. 6-[4-(2-Fluorophenyl)piperazine-1-yl]-3(2H)-pyridazinone-2-acetyl-2-(4-florobenzal)hydrazon (T10)
3.2.9. 6-[4-(2-Fluorophenyl)piperazine-1-yl]-3(2H)-pyridazinone-2-acetyl-2-(4-methoxybenzal)hydrazon (T11)
3.2.10. 6-[4-(2-Fluorophenyl)piperazine-1-yl]-3(2H)-pyridazinone-2-acetyl-2-(2-methylbenzal)hydrazon (T12)
3.3. Enzyme Assays
3.4. Enzyme Inhibitions and Kinetics
3.5. Analysis of Inhibitor Reversibilities
3.6. Cytotoxicity
3.7. Molecular Docking Studies
3.8. ADME Prediction
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Conflicts of Interest
References
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Sample Availability: Samples of the compounds are available from the authors. |
Compound No. | R | Yield (%) | P | MM | Molecular Formula |
---|---|---|---|---|---|
T1 | H | 79.90 | 226–228 | 434.48 | C23H23FN6O2 |
T2 | 4-CH3 | 78.15 | 198–200 | 448.49 | C24H25FN6O2 |
T3 | 2-Cl | 73.19 | 203–205 | 468.91 | C23H22ClFN6O2 |
T4 | 4-Cl | 91.21 | 192–194 | 468.91 | C23H22ClFN6O2 |
T5 | 4-Br | 85.69 | 209–211 | 513.36 | C23H22BrFN6O2 |
T6 | 2-CH3O | 77.45 | 239–241 | 464.49 | C24H25FN6O3 |
T7 | 4-N(CH3)2 | 68.77 | 237–239 | 477.53 | C25H28FN7O2 |
T8 | 3-Br | 90.08 | 207–208 | 513.36 | C23H22BrFN6O2 |
T9 | 2-F | 88.36 | 225–226 | 452.47 | C23H22 F2N6O2 |
T10 | 4-F | 57.70 | 178–180 | 452.47 | C23H22 F2N6O2 |
T11 | 4- OCH3 | 75.32 | 148–150 | 464.49 | C24H25FN6O3 |
T12 | 2-CH3 | 72.21 | 244–245 | 448.49 | C24H25FN6O2 |
Compounds | Residual Activity (%) | IC50 (µM) | SI b | ||
---|---|---|---|---|---|
MAO-A | MAO-B | MAO-A | MAO-B | ||
(10 µM) | (1.0 µM) | ||||
T1 | 96.6 ± 1.20 | 99.4 ± 0.85 | - | 7.68 ± 0.14 | - |
T2 | 24.6 ± 2.86 | 4.22 ± 0.85 | 4.29 ± 0.12 | 0.10 ± 0.035 | 42.9 |
T3 | 24.6 ± 0.97 | 3.01 ± 0.85 | 4.19 ± 0.27 | 0.039 ± 0.0028 | 107.4 |
T4 | 75.2 ± 4.70 | 6.00 ± 0.94 | - | 0.099 ± 0.0069 | - |
T5 | 84.0 ± 0.68 | 54.0 ± 2.83 | - | 1.68 ± 0.11 | - |
T6 | 20.7 ± 0.62 | −15.3 ± 0.94 | 1.57 ± 0.80 | 0.013 ± 0.0016 | 120.8 |
T7 | 25.4 ± 6.92 | 57.8 ± 9.58 | 4.43 ± 0.29 | 0.87 ± 0.056 | - |
T8 | 73.3 ± 2.86 | 67.2 ± 9.58 | - | 2.67 ± 0.051 | - |
T9 | 35.2 ± 0.56 | 2.60 ± 0.74 | 6.76 ± 0.46 | 0.20 ± 0.0017 | 33.8 |
T10 | 33.7 ± 4.70 | 95.3 ± 6.70 | 7.35 ± 0.059 | 35.3 ± 0.39 | 0.21 |
T11 | 70.4 ± 8.50 | 61.1 ± 2.98 | - | 6.86 ± 0.37 | - |
T12 | 61.8 ± 1.65 | 17.9 ± 5.95 | - | 0.15 ± 0.021 | - |
Toloxatone | 1.08 ± 0.025 | - | |||
Lazabemide | - | 0.14 ± 0.011 | |||
Clorgyline | 0.0070 ± 0.00070 | - | |||
Pargyline | - | 0.030 ± 0.00083 |
Compounds | Docking Score (kcal/mol) | |
---|---|---|
MAO-A | MAO-B | |
T3 | −8.20 | −9.45 |
T6 | −8.43 | −9.56 |
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Çeçen, M.; Oh, J.M.; Özdemir, Z.; Büyüktuncel, S.E.; Uysal, M.; Abdelgawad, M.A.; Musa, A.; Gambacorta, N.; Nicolotti, O.; Mathew, B.; et al. Design, Synthesis, and Biological Evaluation of Pyridazinones Containing the (2-Fluorophenyl) Piperazine Moiety as Selective MAO-B Inhibitors. Molecules 2020, 25, 5371. https://doi.org/10.3390/molecules25225371
Çeçen M, Oh JM, Özdemir Z, Büyüktuncel SE, Uysal M, Abdelgawad MA, Musa A, Gambacorta N, Nicolotti O, Mathew B, et al. Design, Synthesis, and Biological Evaluation of Pyridazinones Containing the (2-Fluorophenyl) Piperazine Moiety as Selective MAO-B Inhibitors. Molecules. 2020; 25(22):5371. https://doi.org/10.3390/molecules25225371
Chicago/Turabian StyleÇeçen, Muhammed, Jong Min Oh, Zeynep Özdemir, Saliha Ebru Büyüktuncel, Mehtap Uysal, Mohamed A. Abdelgawad, Arafa Musa, Nicola Gambacorta, Orazio Nicolotti, Bijo Mathew, and et al. 2020. "Design, Synthesis, and Biological Evaluation of Pyridazinones Containing the (2-Fluorophenyl) Piperazine Moiety as Selective MAO-B Inhibitors" Molecules 25, no. 22: 5371. https://doi.org/10.3390/molecules25225371