Structure of 5847-59-6
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Quinolone-3-amidoalkanol: A New Class of Potent and Broad-Spectrum Antimicrobial Agent
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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CAS No. : | 5847-59-6 |
Formula : | C6H4BrNO3 |
M.W : | 218.00 |
SMILES Code : | C1=CC(=CC(=C1O)Br)[N+]([O-])=O |
MDL No. : | MFCD06656567 |
InChI Key : | DCIPFSYBGTWYCR-UHFFFAOYSA-N |
Pubchem ID : | 22109 |
GHS Pictogram: |
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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: | Ⅲ |
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 | 44.99 |
TPSA ? Topological Polar Surface Area: Calculated from |
66.05 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.47 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
2.36 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
2.06 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
1.05 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
-0.1 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.37 |
Log S (ESOL):? ESOL: Topological method implemented from |
-3.02 |
Solubility | 0.21 mg/ml ; 0.000964 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-3.39 |
Solubility | 0.0894 mg/ml ; 0.00041 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-2.06 |
Solubility | 1.89 mg/ml ; 0.00867 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) |
Yes |
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 |
-5.95 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 |
0.0 |
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 |
2.0 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) |
1.88 |
* 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 |
---|---|---|
90% | With 1,2-ethanediylbis(triphenylphosphonium) ditribromide; In methanol; dichloromethane; at 20℃; for 0.0833333h; | General procedure: To a mixture of anilines or phenols (0.7 mmol) the brominatingagent (1) (0.72 g, 0.7 mmol) in dichloromethane(30 ml)-methanol (15 ml) was added. The reactionmixture was stirred at room temperature until decolorizationof the orange solution took place. The progress of thereaction was monitored by TLC (eluent: n-hexane/ethylacetate, 7:3). After completion of the reaction, the solventwas evaporated and diethyl ether (10 ml) was added to theresidue. The supernatant was decanted and the insolubleresidue was washed by ether (3 × 10 ml). The combinedether extracts were dried on magnesium sulfate and also evaporated under vacuum to afford monobromo anilines ormonobromo phenols which was purified by flash columnchromatography over silica gel (n-hexane/ethyl acetate,7:3). |
90% | With 1,2-diphenyl-1,1,2,2-tetrahydroperoxyethane; hydrogen bromide; In water; acetonitrile; at 20℃; for 2.33333h; | General procedure: To a solution of aniline/phenol (1 mmol) in CH3CN (4 mL), HBr and THPDPE (depending on the substrate as shown in Table 7) were added and the solution was stirred at room temperature. After the reaction was completed, Na2SO3 (3M, 1mL) was added to the stirring mixture followed by the addition of H2O (10 mL). The solution was stirred until the desired precipitates appeared. The products were filtered and more purification was carried out using silica- packed column chromatography (Hexane-EtOAc). All of the products were characterized on the basis of their melting points, IR, 1H NMR, and 13C NMR spectral analysis and compared with those reported |
80% | With o-xylylene bis(triethylammonium tribromide); In acetonitrile; at 20℃; for 0.116667h; | General procedure: To a magnetic solution of aromatic compound (1 mmol)in acetonitrile (5 mL), OXBTEATB (0.233 g, 0.5 mmol) wasadded and stirred at room temperature for the appropriatetime (Table 1). The reaction was monitored by TLC (eluent:n-hexane/ethyl acetate: 5/1). The reaction mixture was transferredinto a separatory funnel after filtration of OXBTEABand was extracted with water (15 mL) and dichloromethane(20 mL). The organic layer was dried over anhydrousNa2SO4, and the solvent was concentrated in a rotary evaporator.The crude product was purified by passing it over acolumn of silica gel using a mixture of n-hexane and ethylacetate as the eluent. In order to regenerate the reagent, whitesolid was treated with liquid bromine. All the product structureswere confirmed by comparison of melting point or 1HNMR spectra with ones reported in the literature [29a-29e]. |
65% | With potassium hydrogensulfate; isoquinolinium dichromate; potassium bromide; In water; at 20℃;Sonication; | General procedure: The general method for ultrasonically assisted brominationreaction is almost similar to conventional reaction as mentionedabove. A centimolar (0.01 mol) organic substrate (phenols,anilines, or acetanilides), 0.001 mol potassium halide(KBr), about 50 mg of dilute KHSO4, and hypervalent Cr(VI) reagent (IQCC or IQDC) were suspended in about30 mL solvent (DCE or ACN) in a previously cleaned roundbottom(R.B) flask placed in a sonicator. The reaction mixtureis sonicated at room temperature about 30-40 min. Progressof the reaction was monitored by TLC technique. Workupprocedure after completion of the reaction mixture is similarto the one described previously. |
51% | With acetic acid; potassium bromide; In water; acetic acid; at 35℃; | General procedure: 0.11 g (1.0 mmol) of 4-methylphenol, 5 mL of acetic acid, 0.5 mL of water, and 0.12 g (1.0 mmol)potassium bromide were placed in round-bottomed flask. Then, 0.19 g (0.2 mmol)ZnAl-BrO3--LDHs was added in the flask under stirring at 35 C. After the addition, stirring wascontinued to the end of reaction (monitored by thin layer chromatography). The residualZnAl-BrO3--LDHs were removed by centrifugation. The product was extracted with 3 × 10 mLdichloromethane. The combined extract was washed with sodium sulfite solution, brine, and dried(Na2SO4). Evaporation of the solvent left the crude product. The crude product was purified bycolumn chromatography over silica gel (ethyl acetate-petroleum ether) to obtain pure product. |
45% | With tetrabutylammomium bromide; isoquinolinium chlorochromate; In water; at 25 - 30℃; for 9h; | General procedure: Phenol (1 mmol, 10 mL) dissolved in 1M PEG-600, isoquinolinium dichromate (IQDC) or isoquinolinium chlorochromate (IQCC) reagent, and tetrabutylammonium halide (TBAX) (1.1 mmol each) were taken in a reaction flask and refluxed with constant stirring at about 25 to 30 C, till the completion of reaction, as as certainedby thin layer chromatography. Then the contents of reaction were diluted with ethyl acetate (10 mL) and separated from aqueous layer. Organic layer was then washed two to three time swith 5 mL water and separated. Finally, the resultant mass is dried over sodium sulphate. The anhydrous ethyl acetate layerwas separated under reduced pressure to give crude product, which was further purified by column chromatography (silicagel, 100-200 mesh) using EtOAc-hexane (3:7). For the separation and recyclization of PEG, aqueous mother liquor (reaction mixture of PEG-600 and water) was treated with ether because PEG is insoluble in ether. The aqueous layer obtained after the removal of ether, was then distilled directly at 100 C to remove water and recover PEG-600. The recovered PEG-600 could be reused for consecutive runs. |
With N-Bromosuccinimide; | A. Synthesis of 2-Bromo-4-nitrophenol 2-Bromo-4-nitrophenol was prepared by reaction of 4-nitrophenol and N-bromosuccinimide. The experimental method of preparation was described by T. Oberhouser in J. Org. Chem. 1997 (62), page 4504. | |
With dihydrogen peroxide; acetic acid; potassium bromide; In water; at 20℃; for 6h; | General procedure: Catalytic reaction was carried out in a 50 mL two necked round bottom flask, which charged with 0.05 g of catalyst, substrate (2 mmol) in acetic acid (5 mL) and KBr (2.2 mmol). 30% H2O2 (2.2 mmol) was then added drop wise to the reaction mixture. The content in the flask was stirred continuously at room temperature. After specified time of the reaction, the catalyst was filtered and the solid was washed with ether. The combined filtrates were washed with saturated sodium bicarbonate solution and then shaken with ether in a separating funnel. The organic extract was dried over anhydrous sodium sulfate. The products were analysed by Varian 3400 gas chromatograph equipped with a 30 m CP-SIL8CB capillary column and a Flame Ionization Detector. Identity of the products was also confirmed by using an Agilent GC-MS. | |
With perchloric acid; dihydrogen peroxide; oxygen; potassium bromide; In water; at 20℃; for 6h; | General procedure: In a typical reaction, aqueous 30% H2O2 (20 mmol) was added to the mixture of substrates (10 mmol) and KBr (20 mmol) taken in 10 mL of water. Catalyst (50 mg) and HClO4 (5 mmol) were added to it and the reaction mixture was stirred at room temperature. An additional 15 mmol HClO4 was added to the reaction mixture in three equal portions at 30 min intervals under continuous stirring. After specified time of the reaction, the catalyst was filtered and the solid was washed with ether. The combined filtrates were washed with saturated sodium bicarbonate solution and then shaken with ether in a separating funnel. The organic extract was dried over anhydrous sodium sulphate. The products were analysed by Varian 3400 gas chromatograph equipped with a 30 m CP-SIL8CB capillary column and a Flame Ionization Detector. | |
With N-Bromosuccinimide; In sulfuric acid; at 0℃; | 4-Nitrophenol (5.00g, 35.9mmol) was dissolved in concentrated sulfuric acid (40ml) at room temperature. The solution was cooled to 0C, and N-bromosuccinimide (6.40g, 36.0mmol) was added portionally. Once the complete conversion was detected, the mixture was poured onto ice. The resulted precipitates were collected by filtration, washed with water, and dried. The above-obtained crude 2-bromo-4-nitrophenol was dissolved in acetone (100ml), and stirred with potassium carbonate (12.5g, 90.4mmol) and benzyl bromide (6.20g, 36.2mmol) under reflux for 5h. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (petroleum ether/ethyl acetate 20:1-9:1) to give the title compound as a light yellow solid (8.38g, 76% for two steps). | |
With N-Bromosuccinimide; | A. Synthesis of 2-bromo-4-nitrophenol 2-bromo-4-nitrophenol is prepared by reaction of 4-nitrophenol with N-brom-succinimide, according to the paper by T. Oberhouser in J. Org. Chem. 62, pp. 4504 and following (1997). | |
With bromine; acetic acid; at 5 - 20℃; for 0.333333h; | General procedure: (ii) To a mixture of 4-nitro-1-naphthanol (10 mmol) inacetic acid (25 mL), Br2 (10 mmol, 1.60 g) in acetic acid (5mL) was added dropwise at 5-10oC. The mixture was allowedto stir at room temperature for 20min. The solventwas removed under reduced pressure to yield 3-bromo-4-nitro-1-naphthanol as a yellow solid in 99% yield. It can beused directly for the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With oxalic acid; silica gel; sodium nitrite; In dichloromethane; water; at 20℃; for 0.5h; | 2-bromophenol (20 g, 0.116 mol), sodium nitrite (48 g, 0.696 mol)Oxalic acid (43.7 g, 0.347 mol) was dissolved in 500 ml of dichloromethane,Add SiO211.5g under stirring, and then slowly add the water 11.5ml,After stirring, continue stirring at room temperature for 30 min. The reaction solution is directly filtered,The filter cake was washed twice with dichloromethane and 200 ml / time. The organic layer was dried over anhydrous sodium sulfate,Filtered and evaporated to dryness under reduced pressure to give 27.8 g of crude product,By petroleum ether column chromatography can get the main product 7.2g (TLC a main point, with a small amount of bit impurity). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With iron; ammonium chloride; In methanol; water; | Example 191 3-{3-bromo-4-[3-(1-pyrrolidinyl)propoxy]phenyl}-2-methyl 5-(trifluoromethyl)-4(3H)-quinazolinone (1) Manufacture of 4-amino-2-bromophenol The target compound was obtained by reducing <strong>[5847-59-6]2-bromo-4-nitrophenol</strong> with iron in a mixed solution of methanol and ammonium chloride aqueous solution. <strong>[5847-59-6]2-bromo-4-nitrophenol</strong> was manufactured by the method described in the literature (J. Org. Chem., Vol. 62, 1997, p. 4504). | |
With sodium tetrahydroborate; In tetrahydrofuran; water; at 20℃; for 0.5h; | General procedure: A mixture of 3 mL of 0.015 mol L-1 aromatic nitro compound dissolved in tetrahydrofuran (THF), an aliquot of palladium nanoparticles, 300 muL of 2.0 mol L-1 NaCl solution and an aliquot of water were added into a reaction flask, totalizing 9 mL. Then, 900 muL of 0.5 mol L-1 NaBH4 solution freshly prepared was added to the above solution under continuous stirring. The final ratio H2O:THF was 2.3:1. The mixture was stirred at room temperature for 30 min. After this time, diethyl ether was added and the organic phase was separated and analyzed by gas chromatography (GC/MS) (chromatograph AgilentTechnologies model 7820A coupled to mass spectrometer Agilent Technologies model 5975, operating with acolumn HP5-ms). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
(2) A portion (2.3 g, 10.6 mmol) of the 2-bromo-4-nitrophenol produced in (1) above and 1,2-dibromoethane (7.9 g, 42.1 mmol) were added to N,N-dimethylformamide (20 ml); to the mixture, potassium carbonate (1.6 g) was added, followed by stirring at 80-85 C. for 3 h. The reaction mixture was added to water (100 ml) and extraction was conducted with ethyl acetate, followed by the drying of the extract with magnesium sulfate and concentration. The residue was subjected to column chromatography using a 10:3:1 solvent system of n-hexane, ethyl ether and ethyl acetate as an eluent to yield the end compound 1-(2-bromo-4-nitrophenoxy-2-bromoethane (2.14 g). 1 H-NMR (CDCl3): delta8.47(s,1H), 8.21(d,1H), 6.96(d,1), 4.42(m,2H), 3.71(m,2H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium chloride; In tetrahydrofuran; ethyl acetate; Petroleum ether; | B. Synthesis of 2-Bromo-1-methoxymethoxy-4-nitrobenzene A total of 4.2 g (140 mmoles) of a sodium hydride dispersion (55% in oil) was added portionwise to a solution of 15.3 g (70.0 mmoles) of <strong>[5847-59-6]2-bromo-4-nitrophenol</strong> from step A in 250 mL of tetrahydrofuran (THF) at 0 C. The reaction mixture was then allowed to agitate 50 min at 0 C. after which 1.83 g (19.4 mmoles) of chloromethyl methyl ether was added. The mixture was allowed to agitate for an additional hour at 0 C. after which it was worked up. To this end, the reaction mixture was poured onto ice and extracted with ethyl acetate. The organic phase was washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate, filtered and concentrated. The residue was purified on silica gel using petroleum ether/ethyl acetate (9:1) [as eluent]. This gave 15.8 g (80% of the theoretical) of 2-bromo-1-methoxymethoxy-4-nitrobenzene. 1H-NMR (300 MHz, CDCl3):delta=8.48 (s, 1H); 7.08 (d,1H); 8.16 (d, 1H); 7.26 (d, 1H); 5.36 (s, 2H); 3.53 (s, 3H). | |
1.82 g | Reference Example 18 [0620] [0621] Sodium hydride (440 mg) was added to <strong>[5847-59-6]2-bromo-4-nitro-phenol</strong> (2.0 g) in tetrahydrofuran (50 mL) and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added chloromethylmethylether (1.38 mL) and the mixture was further stirred at room temperature for 24 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture and the mixture was extracted with diethylether. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give compound 18-1 (1.82 g). Compound 18-1 (1.0 g) was dissolved in a mixed solution of toluene (19.7 mL) and N,N-dimethylformamide (1.97 mL), morpholine (493 muL), palladium (II) acetate (85.7 mg), 2-dicyclohexylphosphino-2?,4?,6?-triisopropylbiphenyl (363 mg) and sodium tert-butoxide (550 mg) were added thereto, and the mixture was heated at 100 C. for 1 hour using a microwave reaction device [Initiator 60 EXP (400 W), Biotage]. Water was added to the reaction mixture which was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give a residue, which was purified with silica gel column chromatography (hexane/ethyl acetate) to give compound 18-2 (502 mg). 4N Aqueous solution of hydrochloric acid/dioxane (4 mL) was added to compound 18-2 (206 mg) in methanol (5 mL) and the mixture was stirred at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure, dichloromethane (10.5 mL) was added thereto, and the mixture was cooled to 0 C. 2,6-Lutidine (183 muL) and trifluorometanesulfonic acid anhydride (207 muL) were added thereto, and the mixture was stirred for 1 hour. The reaction mixture was further stirred at room temperature for 18 hours, an aqueous solution of potassium hydrogensulfate (2N) was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give compound 18-3 (355 mg). Compound 18-1: Analyzing method SC2, tR 1.021 min, obs MS[M+1] 262.3 Compound 18-2: Analyzing method SA3, tR 4.17 min, obs MS[M+1] 269.2 Compound 18-3: Analyzing method SC2, tR 1.117 min, obs MS[M+1] 357.2 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With potassium carbonate; In acetone; at 60℃; for 12h; | Benzyl bromide (83 mL, 0.702 mmol) was added drop-wise to a solution of 2-bromo-4- nitrophenol (170 g, 0.780 mmol) and potassium carbonate (323 g, 2.34 mmol) in acetone (1 L) and refluxed at 60 C for 12 h. The reaction mixture was filtered through celite and washed with 200 mL ethyl acetate. The solvent was removed, triturated withhexane (400 mL) at 60 C to obtain the title compound.Yield: 190 g (79 %); 1H NMR (300 MHz, DMSO-d6): O 5.37 (5, 2H, CH2), 7.33-7.50 (m, 6H, Ar), 8.27 (dd, J = 2.4 Hz, 9.1 Hz, 1H, Ar), 8.45 (d, J = 2.4 Hz, 1H, Ar). |
With potassium carbonate; In acetone; for 5h;Reflux; | 4-Nitrophenol (5.00g, 35.9mmol) was dissolved in concentrated sulfuric acid (40ml) at room temperature. The solution was cooled to 0C, and N-bromosuccinimide (6.40g, 36.0mmol) was added portionally. Once the complete conversion was detected, the mixture was poured onto ice. The resulted precipitates were collected by filtration, washed with water, and dried. The above-obtained crude <strong>[5847-59-6]2-bromo-4-nitrophenol</strong> was dissolved in acetone (100ml), and stirred with potassium carbonate (12.5g, 90.4mmol) and benzyl bromide (6.20g, 36.2mmol) under reflux for 5h. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (petroleum ether/ethyl acetate 20:1-9:1) to give the title compound as a light yellow solid (8.38g, 76% for two steps). | |
With potassium carbonate; In acetone; at 70℃; for 20h;Sealed tube; | General procedure: (iii) A mixture of 3-bromo-4-nitro-1-naphthanol (1mmol), BnBr (3 mmol, 0.35 mL), and K2CO3 (2 mmol) inacetone (3 mL) was heated to 70oC for 20 h in a sealed tube.The mixture was diluted with ethyl acetate (20 mL), washedwith water (2 x 10 mL), dried over anhydrous Na2SO4 andconcentrated. Hexane (1 mL) was added into the resulting residue to give benzyl protected 3-bromo-4-nitro-1-naphthanol as a yellow solid 5 in ~90% yield. |