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Structure of 2-Hydroxybenzotrifluoride
CAS No.: 444-30-4
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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.
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Keywords: Arylurea derivatives ; Antibacterial properties ; Anti-MRSA activity ; Anti-VRE activity ; Anti-LRSE activity ; Depolarization of bacterial cell membrane
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Purchased from AmBeed: 122536-76-9 ; 936-59-4 ; 135632-53-0 ; 404-71-7 ; 73874-95-0 ; 372-20-3 ; 98-17-9 ; 402-45-9 ; 57260-71-6 ; 122536-77-0 ; 444-30-4 ; 165800-03-3 ; 150-19-6 ; 1195-45-5 ; 2909-38-8 ; 165800-03-3
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CAS No. : | 444-30-4 |
Formula : | C7H5F3O |
M.W : | 162.11 |
SMILES Code : | C1=CC=CC(=C1C(F)(F)F)O |
MDL No. : | MFCD00002222 |
InChI Key : | ZOQOPXVJANRGJZ-UHFFFAOYSA-N |
Pubchem ID : | 67958 |
GHS Pictogram: |
![]() ![]() ![]() |
Signal Word: | Danger |
Hazard Statements: | H228-H302+H312+H332-H315-H318-H335 |
Precautionary Statements: | P210-P240-P241-P261-P264-P270-P271-P280-P301+P312+P330-P302+P352+P312-P304+P340+P312-P305+P351+P338+P310-P332+P313-P370+P378-P403+P233-P405-P501 |
Class: | 4.1 |
UN#: | 1325 |
Packing Group: | Ⅱ |
Num. heavy atoms | 11 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.14 |
Num. rotatable bonds | 1 |
Num. H-bond acceptors | 4.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 33.47 |
TPSA ? Topological Polar Surface Area: Calculated from |
20.23 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.65 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
2.8 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
3.56 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
2.57 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
2.35 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
2.59 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.95 |
Solubility | 0.183 mg/ml ; 0.00113 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-2.88 |
Solubility | 0.213 mg/ml ; 0.00131 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-2.7 |
Solubility | 0.325 mg/ml ; 0.002 mol/l |
Class? Solubility class: Log S scale |
Soluble |
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) |
No |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
No |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
No |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
No |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
No |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-5.3 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
Ghose? Ghose filter: implemented from |
None |
Veber? Veber (GSK) filter: implemented from |
0.0 |
Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
Muegge? Muegge (Bayer) filter: implemented from |
2.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.55 |
PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
Brenk? Structural Alert: implemented from |
0.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<1.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
1.0 |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | With sodium nitrate; sulfuric acid;sodium nitrite; In dichloromethane; | a) Preparation of 2-nitro-6-trifluoromethylphenol 2-trifluoromethylphenol (3.00 g, 18.5 mmol) was dissolved in methylene chloride(40 mL) followed by the addition of sodium nitrate (1.73 g, 20.4 mmol). The addition of sulfuric acid (23 mL/3M) was then made, followed by addition of a catalytic amount of sodium nitrite. The mixture was allowed to stir. After 24 hours, the reaction mixture was diluted with methylene chloride and extracted with water. The organic layer was dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4% MeOH/CH2 Cl2) gave the desired product(1.84 g, 47%). 1 H NMR (CD3 COCD3): delta 8.35 (d, 1H), 7.95 (d, 1H), 7.13 (t, 1H). |
47% | With sodium nitrate; sulfuric acid;sodium nitrite; In dichloromethane; | a)Preparation of 2-nitro-6-trifluoromethylphenol 2-trifluoromethylphenol (3.00 g, 18.5 mmol) was dissolved in methylene chloride(40 mL) followed by the addition of sodium nitrate (1.73 g, 20.4 mmol). The addition of sulfuric acid (23 mL/3M) was then made, followed by addition of a catalytic amount of sodium nitrite. The mixture was allowed to stir. After 24 hours, the reaction mixture was diluted with methylene chloride and extracted with water. The organic layer was dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/CH2 Cl2) gave the desired product(1.84 g, 47%). 1 H NMR (CD3COCD3): d 8.35 (d,1H), 7.95 (d, 1H), 7.13 (t, 1H). |
47% | With sodium nitrate; sulfuric acid;sodium nitrite; In dichloromethane; | a) Preparation of 2-nitro-6-trifluoromethylphenol 2-trifluoromethylphenol (3.00 g, 18.5 mmol) was dissolved in methylene chloride (40 mL) followed by the addition of sodium nitrate (1.73 g, 20.4 mmol). The addition of sulfuric acid (23 mL/3M) was then made, followed by addition of a catalytic amount of sodium nitrite. The mixture was allowed to stir. After 24 hours, the reaction mixture was diluted with methylene chloride and extracted with water. The organic layer was dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/CH2CH2) gave the desired product (1.84 g, 47%). 1H NMR(CD3COCD3): d 8.35 (d, 1H), 7.95 (d, 1H), 7.13 (t, 1H). |
44% | With Concentrated HNO3; In AcOH; | 17A. 2-Nitro-6-(trifluoromethyl)phenol To a solution of commercially available 2-trifluoromethylphenol (2.5 g, 15.42 mmol) in AcOH (3 mL) cooled to 0 C. was added dropwise concentrated HNO3 (1.5 mL). After the addition, the mixture was stirred at at 0 C. for 5 min, at rt for 10 min, then poured into ice/water, and extracted with ether (3*). The combined ether extracts were washed with water, brine, dried (Na2SO4) and concentrated under reduced pressure. The residue was chromatographed (silica gel) eluding with 0% to 10% EtOAc/hexane to yield the title compound (1.4 g, 44% yield). |
44% | With Concentrated HNO3; In acetic acid; | 17A. 2-Nitro-6-(trifluoromethyl)phenol To a solution of commercially available 2-trifluoromethylphenol (2.5 g, 15.42 mmol) in AcOH (3 mL) cooled to 0 C. was added dropwise concentrated HNO3 (1.5 mL). After the addition, the mixture was stirred at at 0 C. for 5 min, at rt for 10 min, then poured into ice/water, and extracted with ether (3*). The combined ether extracts were washed with water, brine, dried (Na2SO4) and concentrated under reduced pressure. The residue was chromatographed (silica gel) eluding with 0% to 10% EtOAc/hexane to yield the title compound (1.4 g, 44% yield). |
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