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Chemical Structure| 367-12-4 Chemical Structure| 367-12-4

Structure of 2-Fluorophenol
CAS No.: 367-12-4

Chemical Structure| 367-12-4

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Product Citations

Product Citations

Berg, Kaja ; Hegde, Pooja ; Pujari, Venugopal ; Brinkmann, Marzena ; Wilkins, David Z. ; Parish, Tanya , et al.

Abstract: The electron transport chain (ETC) in the cell membrane consists of a series of redox complexes that transfer electrons from electron donors to acceptors and couples this electron transfer with the transfer of protons (H+) across a membrane. This process generates proton motive force which is used to produce ATP and a myriad of other functions and is essential for the long-term survival of Mycobacterium tuberculosis (Mtb), the causative organism of tuberculosis (TB), under the hypoxic conditions present within infected granulomas. Menaquinone (MK), an important carrier molecule within the mycobacterial ETC, is synthesized de novo by a cluster of enzymes known as the classic/canonical MK biosynthetic pathway. MenA (1,4-dihydroxy-2-naphthoate prenyltransferase), the antepenultimate enzyme in this pathway, is a verified target for TB therapy. In this study, we explored structure-activity relationships of a previously discovered MenA inhibitor scaffold, seeking to improve potency and drug disposition properties. Focusing our campaign upon three molecular regions, we identified two novel inhibitors with potent activity against MenA and Mtb (IC50 = 13-22 μM, GIC50 = 8-10 μM). These analogs also displayed substantially improved pharmacokinetic parameters and potent synergy with other ETC-targeting agents, achieving nearly complete sterilization of Mtb in combination therapy within two weeks in vivo. These new inhibitors of MK biosynthesis present a promising new strategy to curb the continued spread of TB.

Keywords: 1,4-dihydroxy-2-naphthoate prenyltransferase ; MenA ; MenA inhibitors ; Menaquinone ; Mtb ; Mycobacterium tuberculosis ; Piperidine derivatives ; SAR

Alternative Products

Product Details of [ 367-12-4 ]

CAS No. :367-12-4
Formula : C6H5FO
M.W : 112.10
SMILES Code : OC1=CC=CC=C1F
MDL No. :MFCD00002155
InChI Key :HFHFGHLXUCOHLN-UHFFFAOYSA-N
Pubchem ID :9707

Safety of [ 367-12-4 ]

GHS Pictogram:
Signal Word:Danger
Hazard Statements:H302+H312+H332-H315-H319-H225
Precautionary Statements:P501-P261-P270-P240-P210-P233-P243-P241-P242-P271-P264-P280-P370+P378-P337+P313-P305+P351+P338-P362+P364-P303+P361+P353-P332+P313-P301+P312+P330-P304+P340+P312-P403+P235
Class:3
UN#:1993
Packing Group:Ⅲ

Computational Chemistry of [ 367-12-4 ] Show Less

Physicochemical Properties

Num. heavy atoms 8
Num. arom. heavy atoms 6
Fraction Csp3 0.0
Num. rotatable bonds 0
Num. H-bond acceptors 2.0
Num. H-bond donors 1.0
Molar Refractivity 28.42
TPSA ?

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

20.23 ?2

Lipophilicity

Log Po/w (iLOGP)?

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

1.53
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

1.71
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.

1.9
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

1.84
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

1.79

Water Solubility

Log S (ESOL):?

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

-2.17
Solubility 0.763 mg/ml ; 0.0068 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.

-1.75
Solubility 1.99 mg/ml ; 0.0178 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

-2.04
Solubility 1.02 mg/ml ; 0.0091 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.

-5.77 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

 2.0
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)

 1.0

Application In Synthesis of [ 367-12-4 ]

* 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.

  • Downstream synthetic route of [ 367-12-4 ]

[ 367-12-4 ] Synthesis Path-Downstream   1~13

  • 1
  • [ 367-12-4 ]
  • [ 2040-90-6 ]
  • 2
  • [ 56-45-1 ]
  • [ 367-12-4 ]
  • [ 7423-96-3 ]
  • 3
  • [ 367-12-4 ]
  • [ 127-17-3 ]
  • [ 7423-96-3 ]
  • 4
  • [ 367-12-4 ]
  • [ 363-52-0 ]
YieldReaction ConditionsOperation in experiment
45% O-fluorophenol (20 g, 0.2 mol) was dissolved in acetonitrile (500 mL, dried over molecular sieves) and protected by argon. Anhydrous magnesium chloride (68 g, 0.72 mol) was added with stirring. Triethylamine (150 mL, 1.08 mol) was added and the mixture was exothermic. After stirring for 20 min, paraformaldehyde (42 g) was added and reacted at 50 ° C for 6 h. TLC showed that some of the starting material remained and the reaction time was not changed significantly. The temperature was lowered to room temperature, and a mixture of sodium hydroxide and water (22.8 g of sodium hydroxide dissolved in 80 mL of 7 jO) was added under ice-water bath. Hydrogen peroxide (30 wtpercent, 140 mL) was then slowly added dropwise with significant exotherm to keep the temperature below The reaction mixture was stirred at 30 ° C for 1.5 h, concentrated hydrochloric acid (12 mol / L) was added to adjust the pH value to 1, and the mixture was extracted with ethyl acetate (4 × 100 mL). The combined organic phases were added with saturated aqueous sodium thiosulfate (200 mL) The mixture was stirred for 1 h. The organic phase was separated and the aqueous phase was extracted with ethyl acetate (1 × 100 mL). The combined organic phases were dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography (PE / EtOAc 15: 1 by volume as Eluent) to give 10.3 g of the pale yellow oily liquid (intermediate C-1a) in 45percent yield and recovery of o-fluorophenol 4.3goC-1a: 6H (300MHzeta; CDC13) 6.63-6.45 (3H, m) (D, J = 15.5Etazeta), 120.3 (d, J = 15.5Etazeta) J = 8.9Hz), 111.6 (d, J = 2.6Hz), 108.1 (d, J = 18.4Hz)
7.21 g Under a nitrogen atmosphere, 600 mL of anhydrous tetrahydrofuran was added 16.2 mL of o-fluorophenol, 35 g of MgCl2,50 mL of triethylamine and 16.2 g of paraformaldehyde were added and heated under reflux for 4 h.Cooled to room temperature, dropping 500mL0.05mol / L NaOH solution, all the components dissolved after the drop of 72mL 30percent hydrogen peroxide, the reaction 2h; then add 72mL 30percent H2O2, stirring reaction 6h.Then add 1.0mol / L hydrochloric acid, adjust the pH 4-5, extracted with methylene chloride,The extract was washed three times with 80percent aqueous Na2S2O3 and dried over anhydrous sodium sulfate overnight.The organic solvent was distilled off under reduced pressure, and the residue was separated by silica gel column chromatography,Eluting with methylene chloride and collecting the desired fractions and evaporated to dryness under reduced pressure to give 7.21 g of a crystalline solid as white
7.5 g Under the protection of nitrogen,Add 16 mL of o-fluorophenol to 600 mL of anhydrous tetrahydrofuran.35g MgCl2,50mL of triethylamine and 16g of paraformaldehyde,The reaction was heated to reflux for 4 h.Cool to room temperature,Add 500mL of 0.05mol/L NaOH solution dropwise.After all the components were dissolved, 72 mL of 30percent hydrogen peroxide was added dropwise.Reaction 2h;Add 70mL of 30percent H2O2,The reaction was stirred for 6 h.Then add 1.0 mol/L hydrochloric acid dropwise.Adjust the pH to 4-5,Extracted with dichloromethane,The extract was washed 3 times with an 80percent Na2S2O3 aqueous solution.It was dried over anhydrous sodium sulfate overnight.Evaporating the organic solvent under reduced pressure,The residue was separated by silica gel column chromatography.Elution with dichloromethane,Collect the required components,Evaporation to dryness under reduced pressure gave 7.5 g of white crystals.Intermediate 2.
  • 6
  • [ 367-12-4 ]
  • [ 113-24-6 ]
  • [ 7423-96-3 ]
  • 7
  • [ 57641-66-4 ]
  • [ 367-12-4 ]
  • [ 1251056-84-4 ]
  • 9
  • [ 367-12-4 ]
  • [ 84851-56-9 ]
  • methyl 4-(1-(2-fluorophenoxy)ethyl)benzoate [ No CAS ]
YieldReaction ConditionsOperation in experiment
33% With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃; for 12h; Methyl 4-(l-(2-fluorophenoxy)ethyl) benzoate. To a solution of methyl 4-(l- hydroxyethyl)benzoate (0.9 g, 5 mmol), 2-fluorophenol (627 mg, 5.6 mmol), triphenylphosphine (2.2 g, 8.4 mmol) in tetrahydrofuran (30 mL) was added diisopropyl azodicarboxylate (1.7 g, 8.4 mmol) at 0C. The mixture was stirred at 20C for 12 hours. Water (15 mL) was added to the mixture and then extracted with ethyl acetate (35 mL x 3). The combined organic phase was dried by sodium sulfate, and then filtered. The filtrate was concentrated in vacuo and purified by column chromatography (silica gel, petroleum ether/ethyl acetate = 5: 1) to give methyl 4-(l-(2- fluorophenoxy)ethyl) benzoate (450 mg, 33%).
33% With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃; for 12h; To a solution of methyl 4-(1-hydroxyethyl)benzoate (0.9 g, 5 mmol), 2-fluorophenol (627 mg, 5.6 mmol), triphenylphosphine (2.2 g, 8.4 mmol) in tetrahydrofuran (30 mL) was added diisopropyl azodicarboxylate (1.7 g, 8.4 mmol) at 0 C. The mixture was stirred at 20 C. for 12 hours. Water (15 mL) was added to the mixture and then extracted with ethyl acetate (35 mL×3). The combined organic phase was dried by sodium sulfate, and then filtered. The filtrate was concentrated in vacuo and purified by column chromatography (silica gel, petroleum ether/ethyl acetate=5:1) to give methyl 4-(1-(2-fluorophenoxy)ethyl)benzoate (450 mg, 33%).
  • 12
  • [ 367-12-4 ]
  • [ 70918-54-6 ]
  • 13
  • [ 367-12-4 ]
  • [ 52854-14-5 ]
  • 4-(2-fluorophenoxy)-6-methoxy-5-nitropyrimidine [ No CAS ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate; In acetonitrile; at 80℃; General procedure: <strong>[52854-14-5]4-chloro-6-methoxy-5-nitro-pyrimidine</strong> (Preparation R1a; 1.0 eq.), the appropriate phenol (1.2 eq.), and potassium carbonate (1.2 eq.) were dissolved in acetonitrile. It was stirred at 80 C till completion, then water was added to the reaction mixture. MeCN was evaporated. The residue extracted with DCM. The combined organic phase was dried over MgS04 and evaporated under reduced pressure to give R2a-R2ce.
 

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