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Structure of 402-23-3
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The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
4.5
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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. : | 402-23-3 |
Formula : | C8H6BrF3 |
M.W : | 239.03 |
SMILES Code : | FC(C1=CC(CBr)=CC=C1)(F)F |
MDL No. : | MFCD00000395 |
InChI Key : | MYYYZNVAUZVXBO-UHFFFAOYSA-N |
Pubchem ID : | 123061 |
GHS Pictogram: |
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Signal Word: | Danger |
Hazard Statements: | H314-H290-H227 |
Precautionary Statements: | P501-P210-P234-P264-P280-P370+P378-P390-P303+P361+P353-P301+P330+P331-P363-P304+P340+P310-P305+P351+P338+P310-P403+P235-P406-P405 |
Class: | 8 |
UN#: | 3265 |
Packing Group: | Ⅱ |
Num. heavy atoms | 12 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.25 |
Num. rotatable bonds | 2 |
Num. H-bond acceptors | 3.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 44.28 |
TPSA ? Topological Polar Surface Area: Calculated from |
0.0 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.32 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
3.68 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
4.6 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
4.12 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
3.83 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
3.71 |
Log S (ESOL):? ESOL: Topological method implemented from |
-3.88 |
Solubility | 0.0316 mg/ml ; 0.000132 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-3.37 |
Solubility | 0.102 mg/ml ; 0.000427 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-4.55 |
Solubility | 0.00678 mg/ml ; 0.0000284 mol/l |
Class? Solubility class: Log S scale |
Moderately soluble |
GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg |
Low |
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) |
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) |
Yes |
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 |
-5.15 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 |
1.0 |
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 |
1.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<2.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
1.87 |
* 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 |
---|---|---|
With sodium hydride; In N,N-dimethyl-formamide; at 0 - 20℃; for 0.5h; | Step 1 : methyl l-[3-(trifluoromethyl)benzyl]-lH-indole-7-carboxylate; Methyl lH-indole-7-carboxylate (Ig, 5.71mmol) and l-(bromomethyl)-3-(trifluoromethyl)benzene (956ul, 6.28mmol) were dissolved in DMF (16ml), in an ice bath. 60percent w/w NaH (251mg, 6.28mmol) was added portionwise. The ice bath was removed and the mixture stirred at RT for 30min. The reaction mixture was quenched with NH4Cl(SaL) and <n="24"/>extracted 3 times with ether. The organic layers were combined, washed with water and brine. The compound was purified by flash chromatography on silica gel. IH NMR (500 MHz, DMSO- d6): delta 7.40 (d, IH), 7.25 (s, IH), 7.10 (m, IH), 7.00 (m, 2H), 6.75 (s, IH), 6.65 (t, IH), 6.50 (d, IH), 6.25 (s, IH), 5.25 (s, 2H), 2.05 (d, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85.96% | With potassium carbonate; In acetone; at 20℃; | General procedure: A mixture of 44 (300 mg, 1.56 mmol), K2CO3 (372 mg, 2.34 mmol), and halogenated compound (1 equiv) in acetone (10 mL) was stirred for 0.5-3.5 h at rt. After filtering the mixture and removing the solvent in vacuo, the residue was purified by column chromatography (eluent: hexane/EtOAc 85:15) to obtain the target compounds (11-23) as white solids. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; | Example 11N-hydroxy-4-oxo-3-[3-(trifluoromethyl)benzyl]-3,4-dihydroquinazoline-7-carboxamide; Compound I-16 Step 1: methyl 4-oxo-3-[3-(trifluoromethyl)benzyl]-3,4-dihydroquinazoline-7-carboxylateTo a solution of <strong>[313535-84-1]methyl 4-oxo-3,4-dihydroquinazoline-7-carboxylate</strong> (0.100 g, 0.49 mmol) in DMF (5 mL) was added potassium carbonate (0.135 g, 0.98 mmol) and 3-(trifluoromethyl)benzyl bromide (0.11 mL, 0.74 mmol). The reaction mixture was heated to 60 C. and stirred overnight. The mixture was then cooled to rt and concentrated. Water was added and the reaction mixture was extracted with DCM (15 mL, 3×). The combined organic phases were then washed with water, and brine, dried over anhydrous Na2SO4, filtered and concentrated to afford methyl 4-oxo-3-[3-(trifluoromethyl)benzyl]-3,4-dihydroquinazoline-7-carboxylate. LC-MS: (FA) ES+363.. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 0℃; for 1h;Inert atmosphere; | Synthesis of2-chloro-8-(3-(trifluoromethyl) benzyl)-7, 8-dihydro-6H-pyrimido [5, 4-b] [I, 4] oxazine [0460] To a stirred solution of 2-chloro-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazine (100 mg, 0.58 mmol) in DMF (2 mL) under argon atmosphere were added sodium hydride (28 mg, 1.16 mmol) and l-(bromomethyl)-3-(trifluoromethyl) benzene (167 mg, 0.69 mmol) at 0 C. The reaction mixture was stirred for 30 min at 0 C. After consumption of the starting materials (monitored by TLC), the reaction was quenched with cold water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extracts were washed with brine (5 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was washed with n-pentane (2 x 5 mL) to afford 2-chloro-8-(3-(trifluoromethyl) benzyl)-7, 8- dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazine (150 mg, 78%) as an off-white solid. 1H-NMR (DMSO-< 5, 400 MHz): delta 7.74-7.45 (m, 3H), 7.61-7.59 (m, 2H), 4.85 (s, 2H), 4.20-4.18 (m, 2H), 3.56-3.51 (m, 2H); LCMS: 329.8 (M+l); (column; X-Select CSH C-18 (50 3.0 mm, 3.5 mupiiota); RT 3.86 min 0.05% Aq TFA: ACN; 0.80 mL/min); UPLC (purity): 93.1%; (column; Acquity UPLC BEH C-18 2.1 X 50 mm, 1.7 mupiiota); RT 2.57 min. ACN: 0.025% Aq TFA; 0.5 mL/min; TLC: 30% EtOAc/hexane (R/. 0.4). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
17.2% | 4-(Benzo[d] [1,3]dioxol-5-yl)thiazol-2-amine(2) (1.00 g, 4.54 mmol) and NaH (0.164 g, 6.82 mmol) to THF (15 ml) todissolved and then allowed to react at room temperature for 1 hour under a nitrogen stream. Then slowly added dropwise atroom temperature 3a(trifluoromethyl) benzyl bromide (1.63 g, 6.82 mmol) and allowed to react for 10 minutes. After thereaction was finished, it was concentrated under reduced pressure and extracted three times into a saturated solution ofNaHCO3 is dissolved in ethyl acetate. The ethyl acetate layer was separated and dried with anhydrous Na2SO4, then purifiedby column chromatography (Ethyl acetate: Hexane = 1: 5) to give the compound 1c to give. Yield 17.2% | |
17% | General procedure: A solution of <strong>[185613-91-6]4-(benzo[d][1,3]dioxol-5-yl)thiazol-2-amine</strong> (1.0 equiv) and NaH (1.5 equiv) in THF was stirred at room temperature. After 1 h, benzyl bromide (1.5 equiv) was added and stirring was continued for 10 more min. The reaction progress was monitored by TLC. After completion of the reaction, quenched with saturated NH4Cl solution and extracted with EtOAc, the organic layer was dried over MgSO4, filtered, concentrated invacuo. The residue was purified by silica gel column chromatography (16% EtOAc/hexanes) to afford desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With potassium carbonate; In acetonitrile;Inert atmosphere; Reflux; | Synthesis of ethyl 3-methoxy-4-((3-(trifluoromethyl)benzyl)oxy)benzoate: Into a round bottomed flask equipped with a nitrogen inlet and a magnetic stir bar, potassium carbonate (1.86 g, 13.46 mmol), <strong>[617-05-0]ethyl 4-hydroxy-3-methoxybenzoate</strong> (1.2 g, 6.12 mmol) and CH3CN (26 mL) was added. The mixture was stirred for 30 minutes before 1 -(bromomethyl)- 3-(trifluoromethyl)benzene (1.59 g, 6.65 mmol) was added. The mixture was then stirred at reflux temperature overnight. The reaction mixture was rotary evaporated. Water (100 mL) was then added to the residue and the aqueous was then extracted with EtOAc ( 3 x 50 mL). The combined organic layers were evaporated and then dried in vacuo yielding 2.08 g (96 %) of ethyl 3-methoxy-4-((3-(trifluoromethyl)benzyl)oxy)benzoate as beige solid. 1H NMR (400 MHz, Chloroform-d) delta 7.69 (s, 1H), 7.63 (d, J= 2.0 Hz, 1H), 7.60 (d, J= 2.0 Hz, 1H), 7.57 (d, J= 2.0 Hz, 1H), 7.56 (s, 1H), 7.48 (t, J= 7.7 Hz, 1H), 6.87 (d, J= 8.4 Hz, 1H), 5.22 (s, 2H), 4.34 (q, J= 7.1 Hz, 2H), 3.93 (s, 3H), 1.36 (t, J= 7.1 Hz, 3H). HPLC-MS: Expected: 355 (MH+); Found: 355. |
96% | In a round bottomed flask equipped with a nitrogen inlet and a magnetic stir bar, potassium carbonate (1.86 g, 13.46 mmol), <strong>[617-05-0]ethyl 4-hydroxy-3-methoxybenzoate</strong> (1.2 g, 6.12 mmol) and CH3CN (26 mL) were added. The mixture was stirred for 30 minutes before 1- (bromomethyl)-3-(trifluoromethyl)benzene (1.59 g, 6.65 mmol) was added. The mixture was then stirred at reflux temperature overnight. The reaction mixture was rotary evaporated. Water (100 mL) was then added to the residue and the aqueous was then extracted with EtOAc (3 x 50 mL). The combined organic layers were evaporated and then dried in vacuo yielding 2.08 g (96 %) of ethyl 3-methoxy-4-((3-(trifluoromethyl)benzyl)oxy)benzoate as product. (0368) 1H NMR (400 MHz, Chloroform-d) delta 7.69 (s, 1H), 7.63 (d, J = 2.0 Hz, 1H), 7.60 (d, J = 2.0 Hz, 1H), 7.57 (d, J = 2.0 Hz, 1H), 7.56 (s, 1H), 7.48 (t, J = 7.7 Hz, 1H), 6.87 (d, J = 8.4 Hz, 1H), 5.22 (s, 2H), 4.34 (q, J = 7.1 Hz, 2H), 3.93 (s, 3H), 1.36 (t, J = 7.1 Hz, 3H). (0369) HPLC-MS: Expected: 355 (MH+); Found: 355. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 12.0h; | General procedure: To a stirred solution of intermediate 6 (100 mg, 0.433 mmol) in DMF was added K2CO3 (179 mg, 1.299 mmol) and 3-fluorobenzyl bromide (54 muL, 0.433 mmol) at RT. After stirring for 12 h, the reaction mixture was concentrated to dryness under vacuum and the residue was extracted with CH2Cl2 and water. The organic layer was washed with brine and dried over MgSO4. Then the solution was concentrated to dryness under vacuum and puried via a ash chromatography silica gel plate (petroleum ether/ethyl acetate, 3/1) to afford title compound as a pale yellow solid in 43% yield. |