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Chemical Structure| 619-08-9 Chemical Structure| 619-08-9

Structure of Nitrofungin
CAS No.: 619-08-9

Chemical Structure| 619-08-9

Nitrofungin

CAS No.: 619-08-9

4.5 *For Research Use Only !

Cat. No.: A448613 Purity: 98%

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Product Citations

Product Citations

Dube, Phelelisiwe S. ; Angula, Klaudia T. ; Legoabe, Lesetja J. ; Jordaan, Audrey ; Boitz Zarella, Jan M. ; Warner, Digby F. , et al.

Abstract: Herein, we describe 39 novel quinolone compounds bearing a hydrophilic amine chain and varied substituted benzyloxy units. These compounds demonstrate broad-spectrum activities against acid-fast bacterium, Gram-pos. and -neg. bacteria, fungi, and leishmania parasite. Compound 30 maintained antitubercular activity against moxifloxacin-, isoniazid-, and rifampicin-resistant Mycobacterium tuberculosis, while 37 exhibited low micromolar activities (<1 μg/mL) against World Health Organization (WHO) critical pathogens: Cryptococcus neoformans, Acinetobacter baumannii, and Pseudomonas aeruginosa. Compounds in this study are metabolically robust, demonstrating % remnant of >98% after 30 min in the presence of human, rat, and mouse liver microsomes. Several compounds thus reported here are promising leads for the treatment of diseases caused by infectious agents.

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Product Details of [ 619-08-9 ]

CAS No. :619-08-9
Formula : C6H4ClNO3
M.W : 173.55
SMILES Code : C1=C(Cl)C(=CC=C1[N+]([O-])=O)O
MDL No. :MFCD00043910
InChI Key :BOFRXDMCQRTGII-UHFFFAOYSA-N
Pubchem ID :12074

Safety of [ 619-08-9 ]

GHS Pictogram:
Signal Word:Danger
Hazard Statements:H302-H315-H317-H318-H410
Precautionary Statements:P261-P264-P270-P272-P273-P280-P301+P312+P330-P302+P352-P305+P351+P338+P310-P333+P313-P391-P501
Class:9
UN#:3077
Packing Group:

Computational Chemistry of [ 619-08-9 ] Show Less

Physicochemical Properties

Num. heavy atoms 11
Num. arom. heavy atoms 6
Fraction Csp3 0.0
Num. rotatable bonds 1
Num. H-bond acceptors 3.0
Num. H-bond donors 1.0
Molar Refractivity 42.3
TPSA ?

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

66.05 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

1.35
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

2.26
Log Po/w (WLOGP)?

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

1.95
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.

0.88
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

-0.13
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

1.26

Water Solubility

Log S (ESOL):?

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

-2.68
Solubility 0.365 mg/ml ; 0.0021 mol/l
Class?

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

Soluble
Log S (Ali)?

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

-3.28
Solubility 0.0904 mg/ml ; 0.000521 mol/l
Class?

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

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

-1.81
Solubility 2.66 mg/ml ; 0.0153 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

Yes
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.

-5.75 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

2.0 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)

1.7

Application In Synthesis of [ 619-08-9 ]

* 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 [ 619-08-9 ]
  • Downstream synthetic route of [ 619-08-9 ]

[ 619-08-9 ] Synthesis Path-Upstream   1~2

  • 1
  • [ 619-08-9 ]
  • [ 6959-47-3 ]
  • [ 179687-79-7 ]
YieldReaction ConditionsOperation in experiment
98%
Stage #1: With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 0.5 h;
Stage #2: With potassium iodide In N,N-dimethyl-formamide at 60℃; for 12 h;
2-(Chloromethyl)pyridine hydrochloride (16.4 g, 0.1 mol) and K2CO3 (27.6 g, 0.2 mol) were suspended in DMF (100 mL) and stirred at room temperature for 30 min. 2-Chloro-4-nitrophenol (17.4 g, 0.1 mol) and KI (0.83 g, 5 mol percent) were added in and the reaction mixture was stirred at 60 °C for 12 h. The reaction suspension was diluted with water (400 mL) and the resulting solid was filtered, washed with water and dried to give 2-((2-chloro-4-nitrophenoxy)methyl)pyridine (26 g, 98percent) as a white solid. Mp 149.2–149.9 °C; MS-EI (m/z): 92, 229, 263(M+).
74% With potassium carbonate; sodium iodide In acetonitrileReflux Step 1:
2-((2-chloro-4-nitrophenoxy)methyl)pyridine
2-chloro-4-nitrophenol (3.4 g, 20 mmol), 2-(chloromethyl)pyridine hydrochloride (3.4 g, 21 mmol), potassium carbonate (3.3 g, 24 mmol) and sodium iodide (3.0 g, 20 mmol) were refluxed in acetonitrile (30 mL) overnight.
The reaction mixture was poured into 100 mL of H2O, extracted with ethyl acetate.
The organic phase was washed with saturated brine, dried, evaporated with rotary evaporator, to obtain the crude product.
The crude product was washed with petroleum ether, filtered and dried, and the compound shown in the title (3.9 g, 74percent) was obtained.
1H NMR (CDCl3): δ 8.63 (1H, d, J=4.8 Hz), 8.34 (1H, d, J=2.8 Hz), 8.16-8.14 (1H, m), 7.79-7.76 (1H, m), 7.62-7.60 (1H, m), 7.31-7.27 (1H, m), 7.11 (1H, d, J=9.2 Hz), 5.49 (2H, s).
52% With caesium carbonate; sodium iodide In acetonitrile at 60℃; for 5 h; 2-CHLORO-4-NITRO PHENOL 10G (57.6 MMOL, 1EQ), 2-PYCOLYL CHLORIDE hydrogen chloride 9.45g (57.6 mmol, 1 eq) cesium carbonate 41.3 (126.8 mmol, 2.2 eq) and sodium iodide 8. 64G (57.6 mmol, 1 eq) were suspended in 200 mL acetonitrile. The reaction mixture was stirred at 60°C for 5h. The resulted suspension was filtered and washed with 400 mL water, YIELDING 2- (2-CHLORO-4-NITRO-PHENOXYMETHYL)-PYRIDINE (8G, 52percent) as a red solid. 2- (2-CHLORO-4-NITRO-PHENOXYMETHYL)-PYRIDINE (8 g, 30. 2MMOL, 1 eq) and 8. 44g iron (151.1 mmol, 5 eq) were mixed in 100 mL acetic acid and 50 mL ethyl acetate and were stirred at rt overnight. The reaction mixture was filtered through celite pad. The filtrate was concentrated in vacuo and neutralized with sat. NA2CO3 solution. The solution was extracted with ethyl acetate and the organic layer was washed with brine and concentrated in vacuo. The resulting crude material was purified by flash chromatography eluting with 30percent ethyl acetate/hexane yielding 3. 2G of 3-Chloro-4- (pyridin-2-ylmethoxy)-phenylamine as a white solid (52percent). 1H-NMR (CDCL3) No. 5.18 (s, 2H), 6.50 (dd, 1H), 6.76 (d, 1H),. 6.80 (d, 1H), 7.22 (m, 1 H), 7.64 (d, 1H), 7.73 (td, 1H), 8.55 (m, 1H) ; LCMS RT = 0.89 min; [M+H]+= 235.1.
52% With caesium carbonate; sodium iodide In acetonitrile at 60℃; for 5 h; 2-chloro-4-nitro phenol 1Og (57.6 mmol, leq), 2-pycolyl chloride hydrogen chloride 9.45g (57.6 mmol, 1 equiv) cesium carbonate 41.3 (126.8 mmol, 2.2 equiv) and sodium iodide 8.64g (57.6 mmol, 1 equiv) were suspended in 200 mL acetonitrile. The reaction mixture was stirred at 60°C for 5h. The resulted suspension was filtered and washed with 400 mL water, yielding 2-(2-chloro-4-nitro-phenoxymethyl)-pyridine (8g, 52percent) as a red solid. 2-(2-chloro-4-nitro-phenoxymethyl)-pyridine (8 g, 30.2mmol, 1 equiv) and 8.44g iron (151.1 mmol, 5 equiv) were mixed in 100 mL acetic acid and 50 mL EtOAc and were stirred at rt overnight. The reaction mixture was filtered through a pad of Celite.(R).. The filtrate was concentrated in vacuo and neutralized with saturated Na2CO3 solution. The solution was extracted with EtOAc and the organic layer was washed with brine and concentrated in vacuo. The resulting crude material was purified by flash chromatography eluting with EtOAc/hexane (3:7) to give 3-Chloro-4-(pyridin-2-ylmethoxy)-phenylamine (3.2 g, 52percent) as a white solid. 1H-NMR (CDCl3) δ 5.18 (s, 2H), 6.50 (dd, IH), 6.76 (d, IH),. 6.80 (d, IH), 7.22 (m, IH), 7.64 (d, IH), 7.73 (td, IH), 8.55 (m, IH); LCMS RT = 0.89 min; [M+H]+ = 235.1.
52% With caesium carbonate; sodium iodide In acetonitrile at 60℃; for 5 h; 2-chloro-4-nitro phenol (10 g, 57.6 mmol, 1 equiv), 2-pycolyl chloride hydrogen chloride (9.45 g, 57.6 mmol, 1 equiv), cesium carbonate 41.3 (126.8 mmol, 2.2 equiv) and sodium iodide (8.64 g, 57.6 mmol, 1 equiv) were suspended in 200 mL acetonitrile. The reaction mixture was stirred at 60° C. for 5 h. The resulted suspension was filtered and washed with water (400 mL), yielding 2-(2-chloro-4-nitro-phenoxymethyl)-pyridine (8 g, 52percent) as a red solid.
52% With caesium carbonate; sodium iodide In acetonitrile at 60℃; for 5 h; 2-Chloro-4-nitro phenol 10 g (57.6 mmol, 1 eq), 2-(chloromethyl)pyridine hydrogen chloride 9.45 g (57.6 mmol, 1 equiv), cesium carbonate (41.3 g, 126.8 mmol, 2.2 equiv) and sodium iodide 8.64 g (57.6 mmol, 1 equiv) were suspended in 200 mL acetonitrile. The reaction mixture was stirred at 60 0C for 5 h. The resulted suspension was filtered and washed with 400 mL water, yielding 2-(2-chloro-4-nitro-phenoxymethyl)-pyridine (8 g,52percent) as a red solid.

References: [1] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 11, p. 3090 - 3104.
[2] Patent: US2016/214964, 2016, A1, . Location in patent: Paragraph 0138.
[3] Patent: WO2005/10008, 2005, A1, . Location in patent: Page/Page column 114-115.
[4] Patent: WO2006/23843, 2006, A2, . Location in patent: Page/Page column 64.
[5] Patent: US2010/298297, 2010, A1, . Location in patent: Page/Page column 14.
[6] Patent: WO2006/55268, 2006, A2, . Location in patent: Page/Page column 32.
[7] Research on Chemical Intermediates, 2013, vol. 39, # 7, p. 3105 - 3110.
[8] Patent: EP3181553, 2017, A1, . Location in patent: Paragraph 0209; 0210.
[9] European Journal of Medicinal Chemistry, 2018, vol. 155, p. 316 - 336.
  • 2
  • [ 4377-33-7 ]
  • [ 619-08-9 ]
  • [ 179687-79-7 ]
YieldReaction ConditionsOperation in experiment
52% With hydrogenchloride; caesium carbonate; sodium iodide In acetonitrile at 60℃; for 5 h; Example 71; 4-f [3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino) [1]benzothieno[2,3-d] pyrimidin-7-ol; Step 1. Preparation of 3-Chloro-4-(pyridin-2-ylmethoxy)-phenylamine; EPO <DP n="84"/> 2-chloro-4-nitro phenol (10 g, 57.6 mmol, 1 equiv), 2-pycolyl chloride hydrogen chloride (9.45 g, 57.6 mmol, 1 equiv) cesium carbonate 41.3 (126.8 mmol, 2.2 equiv) and sodium iodide (8.64 g, 57.6 mmol, 1 equiv) were suspended in 200 mL acetonitrile. The reaction mixture was stirred at 60°C for 5h. The resulted suspension was filtered and washed with water (400 mL), yielding 2-(2-chloro-4- nitro-phenoxymethyl)-pyridine (8 g, 52percent) as a red solid.2-(2-chloro-4-nitro-phenoxyrnethyl)-pyridine (8 g, 30.2mmol, 1 equiv) and iron (8.44 g, 151.1 mmol, 5 equiv) were mixed in acetic acid (100 mL ) and EtOAc (50 mL ) and were stirred at rt overnight. The reaction mixture was filtered through a pad of Celite.(R).. The filtrate was concentrated in vacuo and neutralized with saturated Na2CO3 solution. The solution was extracted with EtOAc and the organic layer was washed with brine and concentrated in vacuo. The resulting crude material was purified by flash chromatography eluting with EtOAc/hexane (3:7) to give 3-Chloro- 4-(pyridin-2-ylmethoxy)-phenylamine (3.2 g, 52percent) as a white solid. 1H-NMR (CDCl3) δ 5.18 (s, 2H), 6.50 (dd, 1H), 6.76 (d, 1H),. 6.80 (d, 1H), 7.22 (m, 1H), 7.64 (d, 1H), 7.73 (td, 1H), 8.55 (m, 1H); LCMS RT = 0.89 min, [M+H]+ = 235.1.
References: [1] Patent: WO2006/44524, 2006, A1, . Location in patent: Page/Page column 82-83.
[2] European Journal of Medicinal Chemistry, 2018, vol. 144, p. 330 - 348.
 

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