Synthesis and Biological Evaluation of 2-Phenoxyacetamide Analogues, a Novel Class of Potent and Selective Monoamine Oxidase Inhibitors
Abstract
:1. Introduction
2. Results and Discussion
2.1. Chemistry
2.2. Enzyme Inhibition Studies
Item | R | X | IC50 (μM) | SI b | |
---|---|---|---|---|---|
MAO-A | MAO-B | ||||
1 | Phenyl | O | 69 | 778 | 11.27 |
2 | 2-Naphthalenyl | O | 149 | 542 | 3.64 |
3 | 4-Fluoro-phenyl | O | 92 | 255 | 2.77 |
4 | 4-Chloro-phenyl | O | 490 | 202 | 0.41 |
5 | 2-Chloro-phenyl | O | 98 | 694 | 7.08 |
6 | 4-Formyl-phenyl | O | 89 | 457 | 5.13 |
7 | 2-Formyl-phenyl | O | 142 | 559 | 3.94 |
8 | 3,4-Dimethyl-phenyl | O | 113 | 534 | 4.73 |
9 | 2-Methyl-phenyl | O | 26 | 663 | 25.5 |
10 | 4-Methyl-phenyl | O | 3 | 541 | 180 |
11 | 2-Methoxy-phenyl | O | 96 | 775 | 8.07 |
12 | 4-Methoxy-phenyl | O | 4 | 980 | 245 |
13 | o-Carboxyphenyl | O | 217 | 177 | 0.82 |
14 | o-Acid ester | O | 108 | 98 | 0.91 |
15 | 4-( N-tert-Butyl O-acyl)amine-phenyl | O | 196 | 296 | 1.51 |
16 | 4-( N-acetyl)amine- phenyl | O | 61 | 553 | 9.07 |
17 | Phenyl | S | 166 | 642 | 3.87 |
18 | 3,4-Dimethyl-phenyl | S | 292 | 366 | 1.58 |
19 | 4-(4,5-dihydro-1H-imidazol-2-yl)-phenyl | O | 61 | 506 | 8.30 |
20 | 2-(4,5-dihydro-1H-imidazol-2-yl)-phenyl | O | 186 | 714 | 3.84 |
21 | 4-((Prop-2-ynylimino)methyl)-phenyl | O | 0.018 | 0.076 | 4.22 |
22 | 4-((Prop-2-ynylamino)methyl)-phenyl | O | 0.094 | 0.164 | 1.74 |
23 | 4-((benzylimino)methyl)-phenyl | O | 96 | 575 | 5.99 |
24 | 4-((benzylamino)methyl)-phenyl | O | 37 | 534 | 14.43 |
25 | 2-((Prop-2-ynylimino)methyl)-phenyl | O | 0.068 | 0.176 | 2.59 |
26 | 2-((Prop-2-ynylamino)methyl)-phenyl | O | 0.168 | 0.188 | 1.19 |
27 | 2-((benzylimino)methyl)-phenyl | O | 147 | 562 | 3.82 |
28 | 2-((benzylamino)methyl)-phenyl | O | 107 | 497 | 4.64 |
Clorgyline | 0.0011 (0.0014) | ||||
Pargyline | 0.0035 (0.0038) |
Enzymes/Cell Lysates | 12 | 21 | 22 | 25 |
---|---|---|---|---|
SH-SY5Y | 5.4 | 0.18 | 0.26 | 0.88 |
MAO-A | 4.0 | 0.018 | 0.094 | 0.068 |
HepG2 | N.D. b | 0.41 | 0.53 | 1.81 |
MAO-B | 980 | 0.076 | 0.164 | 0.176 |
2.3. Reversibility of Inhibition
Compound | MAO-A Inhibiton (%) | MAO-B Inhibiton (%) | ||
---|---|---|---|---|
Before Washing | After Washing | Before Washing | After Washing | |
12 (100 nM) | 88.7% | 12.5% | 96.9% | 8.6% |
Safinamide (100 nM) | 36.1% | 9.8% | 91.3% | 7.1% |
3. Experimental Section
3.1. Materials and Methods
3.2. General Procedure for the Synthesis of Derivatives of Acetamides [15]
3.2.1. General Procedure for the Preparation of Compounds 1–18
3.2.2. Preparation of Compounds 19 and 20
3.2.3. Preparation of Compounds 21, 23 or 25
3.2.4. Preparation of Compound 22, 24 or 26
3.3. Biochemistry
3.3.1. MAOs Inhibitory Assay
3.3.2. Cell Lysates Preparation
3.3.3. Reversibility Experiments
4. Conclusions
Acknowledgments
Author Contributions
Conflicts of Interest
References
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Shen, W.; Yu, S.; Zhang, J.; Jia, W.; Zhu, Q. Synthesis and Biological Evaluation of 2-Phenoxyacetamide Analogues, a Novel Class of Potent and Selective Monoamine Oxidase Inhibitors. Molecules 2014, 19, 18620-18631. https://doi.org/10.3390/molecules191118620
Shen W, Yu S, Zhang J, Jia W, Zhu Q. Synthesis and Biological Evaluation of 2-Phenoxyacetamide Analogues, a Novel Class of Potent and Selective Monoamine Oxidase Inhibitors. Molecules. 2014; 19(11):18620-18631. https://doi.org/10.3390/molecules191118620
Chicago/Turabian StyleShen, Wei, Shian Yu, Jiaming Zhang, Weizheng Jia, and Qing Zhu. 2014. "Synthesis and Biological Evaluation of 2-Phenoxyacetamide Analogues, a Novel Class of Potent and Selective Monoamine Oxidase Inhibitors" Molecules 19, no. 11: 18620-18631. https://doi.org/10.3390/molecules191118620