Chasing ChEs-MAO B Multi-Targeting 4-Aminomethyl-7-Benzyloxy-2H-Chromen-2-ones
Abstract
:1. Introduction
2. Results
2.1. Chemistry
2.2. In Vitro Screening
3. Discussion
3.1. Structure–Activity Relationships
3.2. AChE Kinetics
3.3. Docking Studies
4. Materials and Methods
4.1. Enzyme Inhibition Assays
4.2. Molecular Modeling
4.3. Chemistry
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Conflicts of Interest
Abbreviations
ACh | acetylcholine |
AChE | acetylcholinesterase |
AD | Alzheimer’s disease |
EtOAc | ethyl acetate |
EU | European Union |
BBB | blood-brain barrier |
BChE | butyrylcholinesterase |
CAS | catalytic anionic subsite |
ChE | cholinesterase |
DIAD | diisopropyl azodicarboxylate |
DIEA | N,N-diisopropylethylamine |
DMF | N,N-dimethylformamide |
DMSO | dimethylsulfoxide |
FAD | flavin adenine dinucleotide |
FDA | Food and Drug Administration |
GABA | γ-amminobutirric acid |
HBA | hydrogen bond acceptor |
HBD | hydrogen bond donor |
HIV | human immunodeficiency virus |
HRMS | high-resolution mass |
MAO A | monoamine oxidase A |
MAO B | monoamine oxidase B |
MTDL | multi-target-directed ligand |
PAS | peripheral anionic subsite |
PD | Parkinson’s disease |
PDB | protein data bank |
Q-TOF | quadrupole-time of flight |
THF | tetrahydrofuran |
TPSA | topological polar surface area |
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Sample Availability: Samples of the compounds 3–27 are available from the authors. |
General structure | entry | R1 | R2 | R3 | MAO A a,b | MAO B a,b | AChE a,c | BChE a,d |
A | 3 | Cl | H | H | 0.65 ± 0.02 | 0.0039 ± 0.0008 | 6.2 ± 0.7 | 43 ± 5% |
4 | NMe2 | H | H | 49 ± 1% | 0.57 ± 0.05 | 6.0 ± 1.5 | 34 ± 5% | |
5 | OMe | H | OMe | 1.0 ± 0.1 | 0.067 ± 0.005 | 11 ± 2 | 20 ± 4% | |
6 | –OCH2O– | H | 1.2 ± 0.1 | 0.0075 ± 0.0001 | 8.5 ± 1.8 | 3.4 ± 2.1 | ||
7 | H | H | H | 0.53 ± 0.01 | 0.0021 ± 0.0002 | 26 ± 5% | 17 ± 1% | |
8 | Br | H | H | 2.31 ± 0.04 | 0.0022 ± 0.0001 | 2.00 ± 0.04 | 2.9 ± 0.4 | |
9 | F | H | H | 1.74 ± 0.04 | 0.0013 ± 0.0001 | 2.7 ± 1.0 | 4.8 ± 0.3 | |
General structure | entry | R1 | R2 | MAO A | MAO B | AChE | BChE | |
B | 10 | H | Me | 1.0 ± 0.1 | 0.17 ± 0.01 | 7.2 ± 0.6 | 46 ± 2% | |
11 | Me | H | 0.58 ± 0.03 | 0.068 ± 0.002 | 47.1 ± 0.3% | 48.1 ± 0.6% | ||
12 | Cl | H | 48 ± 1% | 1.0 ± 0.1 | 7.9 ± 0.4 | 27 ± 2% | ||
General structure | entry | R1 | R2 | MAO A | MAO B | AChE | BChE | |
C | 13 | Bn | H | 24 ± 3% | 0.103 ± 0.001 | 17 ± 1 | 3.4 ± 1.3 | |
14 | Bn | Me | 28 ± 1% | 0.332 ± 0.026 | 16 ± 1 | 6.3 ± 0.3 | ||
15 | pyrrolidin-1-yl | 1.12 ± 0.01 | 0.152 ± 0.020 | 6.6 ± 0.9 | 14 ± 2% | |||
16 | 4-methylpiperazin-1-yl | 32 ± 5% | 0.273 ± 0.011 | 3.1 ± 0.6 | 2.3 ± 0.9 | |||
17 | morpholin-1-yl | 32 ± 3% | 0.172 ± 0.001 | 6.6 ± 1.1 | 46 ± 2% | |||
18 | H | H | 46 ± 3% | 0.066 ± 0.015 | 17 ± 4 | 20 ± 7% | ||
19 | Me | Me | 9.2 ± 0.7 | 0.213 ± 0.002 | 8.3 ± 2.0 | 7.0 ± 1.1 | ||
20 | nPr | H | 48 ± 1% | 0.0094 ± 0.0035 | 4.9 ± 1.4 | 3.6 ± 0.8 | ||
21 | nBu | H | 41 ± 3% | 0.164 ± 0.002 | 39 ± 1% | 4.8 ± 0.3 | ||
22 | CH2C≡CH | H | 1.1 ± 0.1 | 0.0041 ± 0.0011 | 2.1 ± 0.2 | 33 ± 6% | ||
23 | CH2C≡CH | Me | 1.7 ± 0.1 | 0.084 ± 0.002 | 5.6 ± 0.7 | 28 ± 1% | ||
24 | CH2CONH2 | H | 0.077 ± 0.014 | 0.061 ± 0.013 | 2.2 ± 0.7 | 13 ± 2% | ||
25 | CH2CONHMe | H | 2.6 ± 0.1 | 0.0011 ± 0.0003 | 5.3 ± 1.4 | <5% | ||
26 | CH2CONMe2 | H | 2.5 ± 0.5 | 0.030 ± 0.001 | 4.3 ± 0.6 | 34 ± 2% | ||
D | 27 | CH2CONH2 | OMe | 5.9 ± 0.5 | 0.013 ± 0.001 | 4.4 ± 0.8 | 41 ± 2% | |
safinamide | 18 ± 3% | 0.031 ± 0.001 | ||||||
donepezil | 0.021 ± 0.002 | 2.3 ± 0.2 |
Entry | MW a | TPSA (Å2) a | HBA a | HBD a | cLogP b | BBB c | RO5 violation a |
---|---|---|---|---|---|---|---|
6 | 339.34 | 69.93 | 6 | 1 | 2.89 | + | 0 |
8 | 374.23 | 51.47 | 4 | 1 | 3.80 | + | 0 |
9 | 313.32 | 51.47 | 5 | 1 | 3.08 | + | 0 |
16 | 398.88 | 45.92 | 5 | 0 | 3.53 | + | 0 |
20 | 357.83 | 51.47 | 4 | 1 | 4.69 | + | 0 |
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Rullo, M.; Catto, M.; Carrieri, A.; de Candia, M.; Altomare, C.D.; Pisani, L. Chasing ChEs-MAO B Multi-Targeting 4-Aminomethyl-7-Benzyloxy-2H-Chromen-2-ones. Molecules 2019, 24, 4507. https://doi.org/10.3390/molecules24244507
Rullo M, Catto M, Carrieri A, de Candia M, Altomare CD, Pisani L. Chasing ChEs-MAO B Multi-Targeting 4-Aminomethyl-7-Benzyloxy-2H-Chromen-2-ones. Molecules. 2019; 24(24):4507. https://doi.org/10.3390/molecules24244507
Chicago/Turabian StyleRullo, Mariagrazia, Marco Catto, Antonio Carrieri, Modesto de Candia, Cosimo Damiano Altomare, and Leonardo Pisani. 2019. "Chasing ChEs-MAO B Multi-Targeting 4-Aminomethyl-7-Benzyloxy-2H-Chromen-2-ones" Molecules 24, no. 24: 4507. https://doi.org/10.3390/molecules24244507