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Structure of 402-49-3
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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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La Rosa, Chris ; Sharma, Pankaj ; Dar, M Junaid ; Jin, Yiru ; Qin, Lingli ; Roy, Anuradha , et al.
Abstract: CYP5122A1, an enzyme involved in sterol biosynthesis in Leishmania, was recently characterized as a sterol C4-methyl oxidase. Screening of a library of compounds against CYP5122A1 and CYP51 from Leishmania resulted in the identification of two structurally related classes of inhibitors of these enzymes. Analogs of screening hit N-(3,5-dimethylphenyl)-4-(pyridin-4-ylmethyl)piperazine-1-carboxamide (4a) were generally strong inhibitors of CYP51 but were less potent against CYP5122A1 and typically displayed weak inhibition of L. donovani promastigote growth. Analogs of screening hit N-(4-(benzyloxy)phenyl)-4-(2-(pyridin-4-yl)ethyl)piperazine-1-carboxamide (18a) were stronger inhibitors of both CYP5122A1 and L. donovani promastigote proliferation but also remained selective for inhibition of CYP51. Two compounds in this series, N-(4-((3,5-bis(trifluoromethyl)benzyl)oxy)phenyl)-4-(2-(pyridin-4-yl)ethyl)piperazine-1-carboxamide (18e) and N-(4-((3,5-di-tert-butylbenzyl)oxy)phenyl)-4-(2-(pyridin-4-yl)ethyl)piperazine-1-carboxamide (18i) showed modest selectivity for inhibiting L. donovani promastigote proliferation compared to J774 macrophages and were effective against intracellular L. donovani with EC50 values in the low micromolar range. Replacement of the 4-pyridyl ring present in 18e with imidazole resulted in a compound (4-(2-(1H-imidazol-1-yl)ethyl)-N-(4-((3,5-bis(trifluoromethyl)benzyl)oxy)phenyl)piperazine-1-carboxamide, 18p) with approximately fourfold selectivity for CYP5122A1 over CYP51 that inhibited both enzymes with IC50 values ≤ 1 µM, although selective potency against L. donovani promastigotes was lost. Compound 18p also inhibited the proliferation of L. major promastigotes and caused the accumulation of 4-methylated sterols in L. major membranes, indicating that this compound blocks sterol demethylation at the 4-position in Leishmania parasites. The molecules described here may therefore be useful for the future identification of dual inhibitors of CYP51 and CYP5122A1 as potential antileishmanial drug candidates and as probes to shed further light on sterol biosynthesis in Leishmania and related parasites.
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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. : | 402-49-3 |
Formula : | C8H6BrF3 |
M.W : | 239.03 |
SMILES Code : | FC(C1=CC=C(CBr)C=C1)(F)F |
MDL No. : | MFCD00000403 |
InChI Key : | IKSNDOVDVVPSMA-UHFFFAOYSA-N |
Pubchem ID : | 123062 |
GHS Pictogram: |
![]() |
Signal Word: | Danger |
Hazard Statements: | H314 |
Precautionary Statements: | P280-P305+P351+P338-P310 |
Class: | 8 |
UN#: | 3261 |
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 |
3.55 |
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 |
3.69 |
Log S (ESOL):? ESOL: Topological method implemented from |
-3.8 |
Solubility | 0.0382 mg/ml ; 0.00016 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-3.24 |
Solubility | 0.139 mg/ml ; 0.000582 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 |
-5.24 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) |
1.74 |
* 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 |
---|---|---|
To a stirred solution of lH-Indole-7-carboxylic acid methyl ester 1 (209.8 g, 1.20 mole) in DMF (1.4 L) at 9 0C was added KOtBu (161.6 g, 1.44 mole) portion wise (temperature rose to 15 0C). The cold bath was removed and the reaction mixture was stirred at r.t. for 2 hours. The reaction mixture was cooled to 10 0C and a solution of l-bromomethyl-4-trifluoromethyl-benzene 2 (343.7g, 1.44 mole) in DMF (400 mL) was added over 2.5 hours and the flask was rinsed with DMF (100 mL). H2O (1.9 L) was added at 15 0C in order to precipitate the product. The slurry was filtered and rinsed with H2O (4 X IL) and the product dried under a flow of N2 under vacuum. 411.1 g of material was obtained at 82 A%. A sample was purified by chromatography : 1H NMR (500 MHz, Acetone-*/*) delta 7.88 (dd, J = 7.8, 1.1 Hz, IH), 7.60 (d, J = 8.2 Hz, IH), 7.58 (d, J = 3.2 Hz, IH), 7.53 (dd, J= 7.5, 1.1 Hz, IH), 7.13 (X, J = 7.6 Hz, IH), 7.07 (d, J = 8.0 Hz, IH), 6.74 (d, J = 3.2 Hz, IH), 5.83 (s, 2H), 3.72 (s, 3H); 19F NMR (377 MHz, Acetone-afe) delta - 62.4; 13C NMR (100 MHz, Acetone-tf6) delta 167.7, 143.8, 132.8, 132.7, 132.2, 128.9 (q, J= 32 Hz), 127.3, 126.0, 125.5 (m), 124.9, 123.3, 119.0, 117.4, 102.8, 52.2, 51.8; IR (CDCl3) 3112, 3076, 3038, 2987, 2949, 2844, 1925, 1716, 1619, 1524, 1448, 1421, 1321, 1275, 1161, 1134, 1113, 1067, 1017, 844, 749, 731cm"1; HRMS-ESI (m / z): [M+H]+ calcd for Ci8H14F3NO2, 334.10494; found 334.10548 | ||
With sodium hydride; In N,N-dimethyl-formamide; at 0 - 20℃; | EXAMPLE 34- { 1 -[( { 1 - [4-(trifluoromethyl)benzyl] - 1 H-indol-7-yl } carbonyl)amino]cyclopropyl } benzoic acidStep 1 : Methyl l-[4-(trifluoromethyl)benzyl]-lH-indole-7-carboxylateMethyl lH-indole-7-carboxylate (47.8 g, 273 mmol) and l-(bromomethyl)-4- (trifluoromethyl)benzene (81 g, 341 mmol) were dissolved in DMF (1.3 L) at O0C. 60% w/w NaH (12 g, 300 mmol) was added portion wise. The ice bath was removed and the mixture stirred at O0C for 3 hours, then overnight at RT. The reaction mixture was quenched with 3 L of NH4Cl(sat.) and the aqueous layer was extracted 3 times with 1 L of ether. The organic layers were combined, washed with water and brine. The compound was purified by flash chromatography on silica gel. 1H NMR (500 MHz, DMSO-d): delta 8.90 (d, IH), 7.70 (s, IH), 7.60 (d, 2H), 7.40 (d, IH), 7.10 (t, IH), 7.00 (d, 2H), 6.70 (d, IH), 5.70 (s, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In acetone; for 15h;Reflux; | 6-(4-Trifluoromethylbenzyloxy)-2-cyanobenzothiazole: A suspension of <strong>[939-69-5]2-cyano-6-hydroxybenzothiazole</strong> (1.0 g, 5.68 mmol) in acetone (5 mL) was prepared in a 100-mL 2-necked round-bottomed flask fitted with a reflux condenser. Anhydrous potassium carbonate (0.94 g, 6.82 mmol) was added to the reaction mixture and the suspension turned to a yellow solution. Then 4-(trifluoromethyl)benzyl bromide (1.49 g, 6.25 mmol) was added and the reaction mixture was heated at reflux for 15 h using a heated stir plate and oil bath. The reaction mixture was allowed to cool to ambient temperature and then filtered to remove inorganic salts. The filtrate was concentrated by rotoevaporation to provide 1.7 g (89percent yield) of an off-white solid that was used without purification. The structure was confirmed by 1H NMR analysis in DMSO-d6 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 0℃; for 0.5h;Inert atmosphere; | Synthesis of2-chloro-8-(4-(trifluoromethyl) benzyl)-7, 8-dihydro-6H-pyrimido [5, 4-b] [I, 4] [0459] To a stirred solution of 2-chloro-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazine (150 mg, 0.87 mmol) in DMF (3 mL) under argon atmosphere were added sodium hydride (42 mg, 1.75 mmol) and l-(bromomethyl)-4-(trifluoromethyl) benzene (251 mg, 1.05 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 100 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-(4-(trifluoromethyl) benzyl)-7, 8- dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazine (220 mg, 76%) as an off-white solid. 1H-NMR (OMSO-d6, 500 MHz): delta 7.76 (s, 1H), 7.74 (d, 2H), 7.52 (d, 2H), 4.89 (s, 2H), 4.23-4.20 (m, 2H), 3.57-3.54 (m, 2H); LCMS: 329.8 (M+l); (column; X-Select CSH C-18 (50 3.0 mm, 3.5 mupiiota); RT 3.88 min 0.05% Aq TFA: ACN; 0.80 mL/min); UPLC (purity): 90.0%; (column; Acquity UPLC BEH C-18 2.1 X 50 mm, 1.7 mupiiota); RT 2.58 min. ACN: 0.025% Aq TFA; 0.5 mL/min; TLC: 30% EtOAc/hexane (R 0.4). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
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. | |
16.7% | 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 to 4-(trifluoromethyl) benzyl bromide (1.63g, 6.82mmol) and the reaction was carried out for 10 minutes.After the reaction was finished, it was concentrated under reduced pressure and extracted three times into a saturatedsolution of NaHCO3 is dissolved in ethyl acetate. The ethyl acetate layer was separated and dried with anhydrous Na2SO4,then purified by column chromatography (Ethyl acetate: Hexane = 1: 5) to give the compound 1d to give. Yield 16.7% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
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 for overnight hours. The reaction mixture was rotary evaporated. Water (100 mL) was then added to the residue and the aqueous was then extracted with EtOAc (50 mL x 3). 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. (0311) lH NMR (400 MHz, Chloroform-d) delta 7.80 - 7.39 (m, 6H), 6.83 (d, J= 8.4 Hz, 1H), 5.24 (0312) (s, 2H), 4.33 (q, J = 7.1 Hz, 2H), 3.93 (s, 3H), 1.36 (t, J = 7.1 Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With caesium carbonate; In N,N-dimethyl-formamide; at 0 - 20℃; for 16h; | A suspension of methyl 1H-indazole-7-carboxylate (1 eq.) and cesium carbonate (3 eq.) in DMF (0.74 M) was cooled to 0°C and 1-(bromomethyl)-4-(trifluoromethyl)benzene (1.2 eq., 0.89M in DMF) was added dropwise. The reaction mixture was allowed to warm slowly to rt over 16 h and then quenched with ice-water and extracted with TBME. The combined organic extracts were washed further with water and brine, dried over MgSO4, and filtered. Concentration of the filtrate in vacuo furnished the crude reaction product as a golden yellow oil, which was purified with column chromatography (Si02, 9:1 (v/v) Hex:EtOAc to EtOAc) to afford the product as a colorless oil (76percent yield). |
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