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Chemical Structure| 57260-71-6 Chemical Structure| 57260-71-6

Structure of N-Boc-piperazine
CAS No.: 57260-71-6

Chemical Structure| 57260-71-6

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Product Citations

Product Citations

Canale, Vittorio ; Czekajewska, Joanna ; Klesiewicz, Karolina ; Papiez, Monika ; Kuziak, Agata ; Witek, Karolina , et al.

Abstract: The alarming increase in the resistance of bacteria to the currently available antibiotics necessitates the development of new effective antimicrobial agents that are active against bacterial pathogens causing major public health problems. For this purpose, our inhouse libraries were screened against a wide panel of clin. relevant Gram-pos. and Gram-neg. bacteria, based on which compound I was selected for further optimization. Synthetic efforts in a group of arylurea derivatives of aryloxy(1-phenylpropyl) alicyclic diamines, followed with an in vitro evaluation of the activity against multidrug-resistant strains identified compound 44 (1-(3-chlorophenyl)-3-(1-{3-phenyl-3-[3-(trifluoromethyl)phenoxy] propyl}piperidin-4-yl)urea). Compound 44 showed antibacterial activity against Gram-pos. bacteria including fatal drug-resistant strains i.e., Staphylococcus aureus (methicillin-resistant, MRSA; vancomycin-intermediate, VISA) and Enterococcus faecium (vancomycin-resistant, VREfm) at low concentrations (0.78-3.125 μg/mL) comparable to last resort antibiotics (i.e., vancomycin and linezolid). It is also potent against biofilm-forming S. aureus and Staphylococcus epidermidis (including linezolid-resistant, LRSE) strains, but with no activity against Gram-neg. bacteria (Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa). Compound 44 showed strong bactericidal properties against susceptible and drug-resistant Gram-pos. bacteria. Depolarization of the bacterial cytoplasmic membrane induced by compound 44 suggests a dissipation of the bacterial membrane potential as its mechanism of antibacterial action. The high antimicrobial activity of compound 44, along with its selectivity over mammalian cells (lung MCR-5 and skin BJ fibroblast cell lines) and no hemolytic properties toward horse erythrocytes, proposes arylurea derivatives of aryloxy(1-phenylpropyl) alicyclic diamines for development of novel antibacterial agents.

Keywords: Arylurea derivatives ; Antibacterial properties ; Anti-MRSA activity ; Anti-VRE activity ; Anti-LRSE activity ; Depolarization of bacterial cell membrane

Purchased from AmBeed: ; ; ; ; ; ; ; ; ; ; ; ; ; ; 165800-03-3 ;

Alternative Products

Product Details of [ 57260-71-6 ]

CAS No. :57260-71-6
Formula : C9H18N2O2
M.W : 186.25
SMILES Code : O=C(N1CCNCC1)OC(C)(C)C
MDL No. :MFCD00075265
InChI Key :CWXPZXBSDSIRCS-UHFFFAOYSA-N
Pubchem ID :143452

Safety of [ 57260-71-6 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H315-H319-H335
Precautionary Statements:P261-P264-P271-P280-P302+P352-P304+P340-P305+P351+P338-P312-P362+P364-P403+P233-P501

Computational Chemistry of [ 57260-71-6 ] Show Less

Physicochemical Properties

Num. heavy atoms 13
Num. arom. heavy atoms 0
Fraction Csp3 0.89
Num. rotatable bonds 3
Num. H-bond acceptors 3.0
Num. H-bond donors 1.0
Molar Refractivity 58.5
TPSA ?

Topological Polar Surface Area: Calculated from
Ertl P. et al. 2000 J. Med. Chem.

41.57 Ų

Lipophilicity

Log Po/w (iLOGP)?

iLOGP: in-house physics-based method implemented from
Daina A et al. 2014 J. Chem. Inf. Model.

2.47
Log Po/w (XLOGP3)?

XLOGP3: Atomistic and knowledge-based method calculated by
XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry

0.46
Log Po/w (WLOGP)?

WLOGP: Atomistic method implemented from
Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.

0.07
Log Po/w (MLOGP)?

MLOGP: Topological method implemented from
Moriguchi I. et al. 1992 Chem. Pharm. Bull.
Moriguchi I. et al. 1994 Chem. Pharm. Bull.
Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.

0.56
Log Po/w (SILICOS-IT)?

SILICOS-IT: Hybrid fragmental/topological method calculated by
FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com

0.52
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

0.82

Water Solubility

Log S (ESOL):?

ESOL: Topological method implemented from
Delaney JS. 2004 J. Chem. Inf. Model.

-1.09
Solubility 15.3 mg/ml ; 0.0819 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Very soluble
Log S (Ali)?

Ali: Topological method implemented from
Ali J. et al. 2012 J. Chem. Inf. Model.

-0.9
Solubility 23.4 mg/ml ; 0.125 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Very soluble
Log S (SILICOS-IT)?

SILICOS-IT: Fragmental method calculated by
FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com

-1.28
Solubility 9.82 mg/ml ; 0.0527 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Soluble

Pharmacokinetics

GI absorption?

Gatrointestinal absorption: according to the white of the BOILED-Egg

High
BBB permeant?

BBB permeation: according to the yolk of the BOILED-Egg

No
P-gp substrate?

P-glycoprotein substrate: SVM model built on 1033 molecules (training set)
and tested on 415 molecules (test set)
10-fold CV: ACC=0.72 / AUC=0.77
External: ACC=0.88 / AUC=0.94

No
CYP1A2 inhibitor?

Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set)
and tested on 3000 molecules (test set)
10-fold CV: ACC=0.83 / AUC=0.90
External: ACC=0.84 / AUC=0.91

No
CYP2C19 inhibitor?

Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set)
and tested on 3000 molecules (test set)
10-fold CV: ACC=0.80 / AUC=0.86
External: ACC=0.80 / AUC=0.87

No
CYP2C9 inhibitor?

Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set)
and tested on 2075 molecules (test set)
10-fold CV: ACC=0.78 / AUC=0.85
External: ACC=0.71 / AUC=0.81

No
CYP2D6 inhibitor?

Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set)
and tested on 1068 molecules (test set)
10-fold CV: ACC=0.79 / AUC=0.85
External: ACC=0.81 / AUC=0.87

No
CYP3A4 inhibitor?

Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set)
and tested on 2579 molecules (test set)
10-fold CV: ACC=0.77 / AUC=0.85
External: ACC=0.78 / AUC=0.86

No
Log Kp (skin permeation)?

Skin permeation: QSPR model implemented from
Potts RO and Guy RH. 1992 Pharm. Res.

-7.11 cm/s

Druglikeness

Lipinski?

Lipinski (Pfizer) filter: implemented from
Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev.
MW ≤ 500
MLOGP ≤ 4.15
N or O ≤ 10
NH or OH ≤ 5

0.0
Ghose?

Ghose filter: implemented from
Ghose AK. et al. 1999 J. Comb. Chem.
160 ≤ MW ≤ 480
-0.4 ≤ WLOGP ≤ 5.6
40 ≤ MR ≤ 130
20 ≤ atoms ≤ 70

None
Veber?

Veber (GSK) filter: implemented from
Veber DF. et al. 2002 J. Med. Chem.
Rotatable bonds ≤ 10
TPSA ≤ 140

0.0
Egan?

Egan (Pharmacia) filter: implemented from
Egan WJ. et al. 2000 J. Med. Chem.
WLOGP ≤ 5.88
TPSA ≤ 131.6

0.0
Muegge?

Muegge (Bayer) filter: implemented from
Muegge I. et al. 2001 J. Med. Chem.
200 ≤ MW ≤ 600
-2 ≤ XLOGP ≤ 5
TPSA ≤ 150
Num. rings ≤ 7
Num. carbon > 4
Num. heteroatoms > 1
Num. rotatable bonds ≤ 15
H-bond acc. ≤ 10
H-bond don. ≤ 5

1.0
Bioavailability Score?

Abbott Bioavailability Score: Probability of F > 10% in rat
implemented from
Martin YC. 2005 J. Med. Chem.

0.55

Medicinal Chemistry

PAINS?

Pan Assay Interference Structures: implemented from
Baell JB. & Holloway GA. 2010 J. Med. Chem.

0.0 alert
Brenk?

Structural Alert: implemented from
Brenk R. et al. 2008 ChemMedChem

0.0 alert: heavy_metal
Leadlikeness?

Leadlikeness: implemented from
Teague SJ. 1999 Angew. Chem. Int. Ed.
250 ≤ MW ≤ 350
XLOGP ≤ 3.5
Num. rotatable bonds ≤ 7

No; 1 violation:MW<1.0
Synthetic accessibility?

Synthetic accessibility score: from 1 (very easy) to 10 (very difficult)
based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties,
trained on 12'782'590 molecules and tested on 40 external molecules (r2 = 0.94)

2.15

Application In Synthesis of [ 57260-71-6 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

  • Upstream synthesis route of [ 57260-71-6 ]
  • Downstream synthetic route of [ 57260-71-6 ]

[ 57260-71-6 ] Synthesis Path-Upstream   1~5

  • 1
  • [ 110-85-0 ]
  • [ 24424-99-5 ]
  • [ 76535-75-6 ]
  • [ 57260-71-6 ]
YieldReaction ConditionsOperation in experiment
60% at 0℃; for 1 h; To a cold methylene chloride solution (10 ml) of piperazine (30.23 mmol, 2.60 g) was added methylene chloride solution (10 ml) of BOC anhydride (1.50 mmol) and the mixture was stirred at 0°C for 1 hour. After the reaction is complete, water is added and the aqueous K2CO3 solution is added to make the reaction mixture basic. All of the reaction mixture was extracted with methylene chloride and the product was isolated by column chromatography.
References: [1] Green Chemistry, 2014, vol. 16, # 7, p. 3635 - 3642.
[2] Journal of Heterocyclic Chemistry, 1990, vol. 27, # 6, p. 1559 - 1563.
[3] Russian Journal of Organic Chemistry, 2009, vol. 45, # 5, p. 788 - 791.
[4] Patent: KR2015/111825, 2015, A, . Location in patent: Paragraph 0722-0734.
[5] Journal of Medicinal Chemistry, 1992, vol. 35, # 21, p. 3845 - 3857.
[6] Journal of Medicinal Chemistry, 1992, vol. 35, # 21, p. 3845 - 3857.
[7] Tetrahedron Letters, 2006, vol. 47, # 46, p. 8039 - 8042.
[8] Patent: KR2016/108281, 2016, A, . Location in patent: Paragraph 0721-0724.
  • 2
  • [ 24424-99-5 ]
  • [ 57260-71-6 ]
  • [ 76535-75-6 ]
References: [1] Journal of Organic Chemistry, 2006, vol. 71, # 21, p. 8283 - 8286.
  • 3
  • [ 124-63-0 ]
  • [ 57260-71-6 ]
  • [ 161357-89-7 ]
References: [1] Patent: US9335320, 2016, B2, . Location in patent: Page/Page column 74.
  • 4
  • [ 57260-71-6 ]
  • [ 118753-66-5 ]
References: [1] Patent: WO2015/22663, 2015, A1, .
[2] European Journal of Medicinal Chemistry, 2018, vol. 158, p. 247 - 258.
[3] Patent: US10213433, 2019, B2, .
  • 5
  • [ 57260-71-6 ]
  • [ 627-18-9 ]
  • [ 132710-90-8 ]
YieldReaction ConditionsOperation in experiment
80% With potassium carbonate In acetonitrile at 95℃; for 4 h; Intermediate 121: tert-Butyl 4-(3-hvdroxypropyr)piperazine-l -carboxylate A mixture of tert-butyl piperazine-1 -carboxylate (2.75 g, 14.8 mmol), l-bromo-3- propanol (1.43 mL, 16.2 mmol) and potassium carbonate (2.25 mL, 27.5 mmol) in acetonitrile (75 mL) was heated at 950C for 4 hours. The solvent was removed under reduced pressure, and the residue was taken up in dichloromethane (300 mL) and washed with water, brine, EPO <DP n="118"/>dried over sodium sulfate and concentrated under reduced pressure. Chromatography on silica gel with methanol in dichloromethane (0-10percent) gave a tan solid 2.88 g (80percent yield). MS (ESV 245 (MH+) for C12H24N2O3,1H-NMR TCDCl1) δ: 1.44 (m, 9H); 1.70-1.82 (m, 2H); 2.40-2.53 (m, 2H); 2.62-2.65 (m, 2H); 3.43-3.50 (m, 4H); 2.77 (m, 2H); 3.73-3.82 (m, 2H).
References: [1] Patent: WO2006/134378, 2006, A1, . Location in patent: Page/Page column 116-117.
 

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