Synthesis, Biological Evaluation and Molecular Docking Studies of Piperidinylpiperidines and Spirochromanones Possessing Quinoline Moieties as Acetyl-CoA Carboxylase Inhibitors
Abstract
:1. Introduction
2. Results and Discussion
2.1. Chemistry
2.2. Biological Activities
Comp. | ACC1 IC50 (nM) a | ACC2 IC50 (nM) a | TC50 (μM) a,b | LogP d | Drug-Likeness Model Score e |
---|---|---|---|---|---|
7a | 189 (±3) | 172 (±7) | >100 | 3.48 | 1.14 |
7b | 750 (±9) | 360 (±10) | >100 | 5.03 | 1.61 |
7c | 940 (±5) | 205 (±9) | >100 | 4.38 | 1.49 |
7d | 620 (±12) | 294 (±3) | >100 | 3.48 | 1.38 |
7e | 750 (±11) | 382 (±15) | >100 | 4.03 | 1.4 |
7f | >1000 | 920 (±14) | N.T. c | 4.54 | 1.37 |
7g | 860 (±3) | 810 (±11) | >100 | 3.42 | 0.85 |
7h | >1000 | >1000 | N.T. c | 4.10 | 1.13 |
7i | >1000 | >1000 | N.T. c | 4.05 | 0.92 |
12a | 600 (±7) | 650 (±12) | >100 | 4.84 | 1.07 |
12b | 760 (±11) | 820 (±14) | >100 | 4.43 | 1.05 |
12c | >1000 | >1000 | N.T. c | 5.18 | 0.73 |
12d | >1000 | 940 | N.T. c | 5.41 | 0.81 |
12e | >1000 | >1000 | N.T. c | 5.46 | 1.04 |
12f | >1000 | >1000 | N.T. c | 3.91 | 0.65 |
12g | >1000 | >1000 | N.T. c | 3.18 | 0.41 |
CP-640186 | 173 (±4) | 185 (±5) | >100 | 3.59 | 0.27 |
2.3. Molecular Docking Study
3. Experimental Section
3.1. General Information
3.1.1. General Procedure for the Preparation of Substituted 1-(Quinoline-4-carbonyl)piperidin-4-ones 3
3.1.2. General Procedure for the Preparation of Substituted (R)-Ethyl 1′-(Quinoline-4-carbonyl)-[1,4′-bipiperidine]-3-carboxylates 5
3.1.3. General Procedure for the Preparation of Substituted (R)-1′-(Quinoline-4-carbonyl)-[1,4′-bipiperidine]-3-carboxamides 7a–7i
3.1.4. General Procedure for the Preparation of Tert-butyl 4-oxospiro[chroman-2,4' piperidine]-1'-carboxylate (10)
3.1.5. General Procedure for the Preparation of Substituted 1′-(Quinoline-4-carbonyl)spiro[chroman-2,4′-piperidin]-4-ones 12a–12g
3.2. Molecular Docking
3.3. ACC1 and ACC2 in Vitro Assay
3.4. In Vitro Cytotoxic Activities
4. Conclusions
Acknowledgments
Author Contributions
Conflicts of Interest
References
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Huang, T.; Sun, J.; Wang, Q.; Gao, J.; Liu, Y. Synthesis, Biological Evaluation and Molecular Docking Studies of Piperidinylpiperidines and Spirochromanones Possessing Quinoline Moieties as Acetyl-CoA Carboxylase Inhibitors. Molecules 2015, 20, 16221-16234. https://doi.org/10.3390/molecules200916221
Huang T, Sun J, Wang Q, Gao J, Liu Y. Synthesis, Biological Evaluation and Molecular Docking Studies of Piperidinylpiperidines and Spirochromanones Possessing Quinoline Moieties as Acetyl-CoA Carboxylase Inhibitors. Molecules. 2015; 20(9):16221-16234. https://doi.org/10.3390/molecules200916221
Chicago/Turabian StyleHuang, Tonghui, Jie Sun, Qianqian Wang, Jian Gao, and Yi Liu. 2015. "Synthesis, Biological Evaluation and Molecular Docking Studies of Piperidinylpiperidines and Spirochromanones Possessing Quinoline Moieties as Acetyl-CoA Carboxylase Inhibitors" Molecules 20, no. 9: 16221-16234. https://doi.org/10.3390/molecules200916221