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Structure of 161975-39-9

Chemical Structure| 161975-39-9

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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 [ 161975-39-9 ]

CAS No. :161975-39-9
Formula : C12H23NO5S
M.W : 293.38
SMILES Code : CC(C)(C)OC(=O)N1CCC(COS(C)(=O)=O)CC1
MDL No. :MFCD02082459
InChI Key :RXNQBVRCZIYUJK-UHFFFAOYSA-N
Pubchem ID :2765838

Safety of [ 161975-39-9 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302-H315-H319-H335
Precautionary Statements:P261-P280-P301+P312-P302+P352-P305+P351+P338

Computational Chemistry of [ 161975-39-9 ] Show Less

Physicochemical Properties

Num. heavy atoms 19
Num. arom. heavy atoms 0
Fraction Csp3 0.92
Num. rotatable bonds 6
Num. H-bond acceptors 5.0
Num. H-bond donors 0.0
Molar Refractivity 76.26
TPSA ?

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

81.29 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

2.96
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

1.28
Log Po/w (WLOGP)?

WLOGP: Atomistic method implemented from
Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.

2.31
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.

1.21
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

0.38
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

1.63

Water Solubility

Log S (ESOL):?

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

-2.07
Solubility 2.5 mg/ml ; 0.00852 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.

-2.59
Solubility 0.76 mg/ml ; 0.00259 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

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

-1.72
Solubility 5.54 mg/ml ; 0.0189 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

No
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

Yes
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.

-7.18 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

0.0
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

1.0 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<0.0
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)

2.88

Application In Synthesis of [ 161975-39-9 ]

* 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 [ 161975-39-9 ]

[ 161975-39-9 ] Synthesis Path-Downstream   1~4

  • 1
  • [ 2346-26-1 ]
  • [ 161975-39-9 ]
  • [ 863286-96-8 ]
YieldReaction ConditionsOperation in experiment
With N,N,N',N'-tetramethylguanidine; In tetrahydrofuran; N,N-dimethyl-formamide; for 24h;Heating / reflux; 2.2. 1,1-dimethylethyl 4-[(2,4-dioxo-1,3-oxazolidin-3-yl)methyl]piperidine-1-carboxylate A suspension of 13.60 g (46.36 mmol) of 1,1-dimethylethyl 4-[(methylsulphonyl)oxy]methyl}piperidine-1-carboxylate, prepared in step 2.1., 9.37 g (92.72 mmol) of 1,3-<strong>[2346-26-1]oxazolidine-2,4-dione</strong> and 16.02 g (139.08 mmol) of 1,1,3,3-tetramethylguanidine in a mixture of 180 ml of tetrahydrofuran and 30 ml of dimethylformamide is heated at reflux for 24 hours. It is allowed to return to ambient temperature and is concentrated under reduced pressure. The residue is taken up in dichloromethane and water and the aqueous phase is separated off and extracted twice with dichloromethane. The combined organic phases are washed with saturated aqueous sodium chloride solution and dried over sodium sulphate. Following evaporation of the solvent, the residue obtained is purified by chromatography on silica gel, eluding with a 98/2 then 95/5 mixture of dichloromethane and methanol. This gives 12.53 g of product in the form of an orange-brown solid.
  • 2
  • [ 161975-39-9 ]
  • [ 4983-28-2 ]
  • [ 1314391-51-9 ]
YieldReaction ConditionsOperation in experiment
95.05% With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 16h;Inert atmosphere; Under nitrogen atmosphere, potassium carbonate (74.12 g, 536.28 mmol) was added into a solution of intermediate 7A (94.40 g, 321.77 mmol) and <strong>[4983-28-2]2-chloropyrimidin-5-ol</strong> (35.00 g, 268.14 mmol) in DMF (1.00 L). The reaction solution was left at 80 C. for 16 hours, and thin layer chromatography was used to detect the completion of the reaction. Then the reaction solution was cooled to room temperature and concentrated, then water (500 mL) was added into the residue and extracted with ethyl acetate (300 mL*3). The organic phase was washed with brine (400 mL*2) and dried over anhydrous sodium sulfate, then filtered and concentrated. Then the residue was purified by column chromatography to give the intermediate 7B (pale yellow solid, 84.00 g, 95.05% yield). LCMS (ESI) m/z: 327.7 (M+1). 1HNMR (400 MHz, DMSO-d6) delta ppm 1.08-1.25 (m, 2H) 1.40 (s, 9H) 1.69-1.78 (m, 2H) 1.88-2.03 (m, 1H) 2.58-2.88 (m, 2H) 3.89-4.05 (m, 4H) 8.50-8.57 (m, 2H)
94% With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 5h; tert-Butyl 4-((methylsulfonyloxy)methyl)piperidin-l-carboxylate (Step 2 of Intermediate 1, 2.00 g, 6.82 mmol) was dissolved in DMF (80 mL). K2C03 (3.33 g, 10.23 mmol) was added thereto, followed by stirring for 5 minutes. 2-Chloropyrimidin-5-ol (890 mg, 6.82 mmol) was added thereto, followed by stirring at 80 C for 5h. To the reaction mixture, water was added, and the mixture was extracted with EtOAc. The organic layer was washed with saturated NH4C1 aqueous solution, dried with anhydrous MgS04, and then concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc hexane = 30 % ~ 70 %) to obtain white solid (2.10 g, 94%).
94% t-butyl 4-((methylsulfonyloxy)methyl)piperidin-1-carboxylate (the product of synthesis step 2 of compound 431; 2.00 g, 6.82 mmol) was dissolved in DMF (80 mL). K2CO3 (3.33 g, 10.23 mmol) was added thereto, and stirred for 5 minutes. <strong>[4983-28-2]2-chloropyrimidin-5-ol</strong> (890 mg, 6.82 mmol) was added thereto, following with stirring at 80 C. for 5 hours. The reaction mixture was added with water, and extracted with EtOAc. The organic layer was washed with saturated NH4Cl aqueous solution, dried over anhydrous MgSO4, and concentrated under reduced pressure. The obtained concentrate was purified by silica gel column chromatography (EtOAchexane=30%?70%) to yield the title compound as white solid (2.10 g, 94%)
With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; To a solution of 4-methanesulfonyloxymethylpiperidine-l-carboxylic acid tert-butyl ester (Preparation 23, 1.47g, 5.0mmol) and <strong>[4983-28-2]2-chloropyrimidin-5-ol</strong> (0.65g, 5.0mmol) in DMF (80mL) was added potassium carbonate (0.83g, 6.0mmol) and the reaction was heated to 80C until complete. The solvent was removed in vacuo, and the resulting residue was re- dissolved in EtOAc (300mL). The solution was washed with 1M NaOH solution (200mL), brine (200mL), then dried (MgS04) and the solvent was removed in vacuo. Purification by column chromatography (IH:EtOAc, 70:30) afforded the title compound: lH NMR delta?(400MHz, CDCI3): 8.30 (s, 1H), 4.18 (br. s., 2H), 3.92 (dd, J=6.25, 3.51 Hz, 2H), 2.78 (t, J=12.30 Hz, 2H), 2.09 - 1.95 (m, 1H), 1.84 (d, J=12.89 Hz, 2H), 1.49 (s, 9H), 1.41 - 1.24 (m,2H).

  • 3
  • [ 161975-39-9 ]
  • [ 189680-06-6 ]
  • tert-butyl 4-((4-bromo-3-cyanophenoxy)methyl)piperidin-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
70% With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 5.0h; tert-butyl 4-((methylsulfonyloxy)methyl)piperidin-1-carboxylate ( 2.00 g, 6.81 mmol), 2-bromo-5- hydroxybenzonitrile (1.35 g, 6.87 mmol) and K2CO3 (1.88 g, 13.63 mmol) were dissolved in DMF (50 mL) at 80 C, following with stirring at the same temperature for 5 hours. The reaction mixture was added with water, and extracted with EtOAc. The organic layer was washed with saturated NH4Cl aqueous solution, dried over anhydrous MgSO4, and filtered. The filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (Si02, 12 g cartridge; EtOAc / hexane = 0 % to 30 %), and concentrated to yield the title compound as white solid (1.90 g, 70%).
70% With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 5.0h; tert-Butyl 4-((methylsulfonyloxy)methyl)piperidin-l-carboxylate (Step 2 of Intermediate 1, 2.00 g, 6.81 mmol), <strong>[189680-06-6]2-bromo-5-hydroxybenzonitrile</strong> (1.35 g, 6.87 mmol) and K2C03 (1.88 g, 13.63 mmol) were dissolved in DMF (50 mL) at 80C. The solution was stirred at the same temperature for 5 h. To the reaction mixture, water was added, and the mixture was extracted with EtOAc. The organic layer was washed with saturated NH4C1 aqueous solution, dried with anhydrous MgS04, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (Si02, 12 g cartridge; EtOAc / hexane = 0 % to 30 %), and concentrated to obtain the desired compound (1.90 g, 70%) as white solid .
70% With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 5.0h; t-butyl 4-((methylsulfonyloxy)methyl)piperidin-1-carboxylate (2.00 g, 6.81 mmol), <strong>[189680-06-6]2-bromo-5-hydroxybenzonitrile</strong> (1.35 g, 6.87 mmol) and K2CO3 (1.88 g, 13.63 mmol) were dissolved in DMF (50 mL) at 80 C., following with stirring at the same temperature for 5 hours. The reaction mixture was added with water, and extracted with EtOAc. The organic layer was washed with saturated NH4Cl aqueous solution, dried over anhydrous MgSO4, and filtered. The filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 12 g cartridge; EtOAchexane=0% to 30%), and concentrated to yield the title compound as white solid (1.90 g, 70%)
  • 4
  • [ 39903-01-0 ]
  • [ 161975-39-9 ]
  • tert-butyl 4-[(2-amino-5-bromopyridin-3-yl)oxy]methyl}piperidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
59 g With caesium carbonate; In N,N-dimethyl-formamide; at 80℃; for 2h; To a mixture of tert-butyl 4-[(methylsulfonyl)oxy]methyl}piperidine-1 -carboxylate (I-48) (54.6 g, 186 mmol) and Cs2C03 (1 10 g, 339 mmol) in DMF (400 mL) was added <strong>[39903-01-0]2-amino-5-bromopyridin-3-ol</strong> (I-53) (32.0 g, 169.3 mol) at room temperature. The resulting mixture was stirred at 80 °C for 2 h. TLC (petroleum ether/ EtOAc = 1 /1) showed the reaction was complete. The reaction mixture was cooled to room temperature and concentrated under high vacuum to dryness. The residue was diluted with 200 mL of water and extracted with CH2CI2 (3 x 200 mL). The combined organic layers were washed with brine (100 mL), dried over Na2S04. The mixture was concentrated under vacuum to give the crude product, which was purified by silica gel chromatography (petroleum ether/ EtOAc = 3/1 to 1 /2) to give tert-butyl 4-[(2-amino-5-bromopyridin-3-yl)oxy]methyl}piperidine-1 -carboxylate (I-54) (59.0 g, 90percent) as a white solid.
 

Historical Records

Technical Information

Categories

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