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Chemical Structure| 6457-49-4 Chemical Structure| 6457-49-4

Structure of 6457-49-4

Chemical Structure| 6457-49-4

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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 [ 6457-49-4 ]

CAS No. :6457-49-4
Formula : C6H13NO
M.W : 115.17
SMILES Code : OCC1CCNCC1
MDL No. :MFCD00174228
InChI Key :XBXHCBLBYQEYTI-UHFFFAOYSA-N
Pubchem ID :420771

Safety of [ 6457-49-4 ]

GHS Pictogram:
Signal Word:Danger
Hazard Statements:H314
Precautionary Statements:P280-P305+P351+P338-P310
Class:8
UN#:3263
Packing Group:

Computational Chemistry of [ 6457-49-4 ] Show Less

Physicochemical Properties

Num. heavy atoms 8
Num. arom. heavy atoms 0
Fraction Csp3 1.0
Num. rotatable bonds 1
Num. H-bond acceptors 2.0
Num. H-bond donors 2.0
Molar Refractivity 36.72
TPSA ?

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

32.26 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

1.62
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

-0.14
Log Po/w (WLOGP)?

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

-0.4
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.

0.21
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

0.96
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

0.45

Water Solubility

Log S (ESOL):?

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

-0.4
Solubility 45.9 mg/ml ; 0.398 mol/l
Class?

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

Very soluble
Log S (Ali)?

Ali: Topological method implemented from
Ali J. et al. 2012 J. Chem. Inf. Model.

-0.08
Solubility 95.1 mg/ml ; 0.825 mol/l
Class?

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

Very 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

-0.86
Solubility 15.8 mg/ml ; 0.137 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

No
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.

-7.1 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

1.0
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

0.0 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<1.0
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)

1.0

Application In Synthesis of [ 6457-49-4 ]

* 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 [ 6457-49-4 ]

[ 6457-49-4 ] Synthesis Path-Downstream   1~10

  • 1
  • [ 4606-65-9 ]
  • [ 6457-49-4 ]
  • [ 103-76-4 ]
  • [ 50-00-0 ]
  • [ 63006-93-9 ]
  • [ 68832-13-3 ]
  • [ 18881-17-9 ]
  • [ 1107174-37-7 ]
  • [ 1106671-44-6 ]
  • [ 1106671-06-0 ]
  • C20H21BrN2O3 [ No CAS ]
  • C23H21NO3S2 [ No CAS ]
  • [ 1106671-83-3 ]
  • [ 1106671-48-0 ]
  • C22H21N3O3S [ No CAS ]
  • C25H20N2O3S [ No CAS ]
  • C27H23NO4S [ No CAS ]
  • C27H24N2O3S [ No CAS ]
  • C26H23N3O3S [ No CAS ]
  • C28H26N2O4S [ No CAS ]
  • [ 135980-88-0 ]
  • [ 124-40-3 ]
  • [ 74-89-5 ]
  • [ 23356-96-9 ]
  • [ 498-63-5 ]
  • [ 958451-07-5 ]
  • [ 958449-79-1 ]
  • [ 958451-09-7 ]
  • [ 958450-34-5 ]
  • [ 958451-15-5 ]
  • [ 958450-40-3 ]
  • [ 958450-35-6 ]
  • [ 958450-41-4 ]
  • [ 958451-11-1 ]
  • [ 958449-81-5 ]
  • [ 958449-68-8 ]
  • [ 958449-67-7 ]
  • [ 958449-66-6 ]
  • [ 958450-36-7 ]
  • [ 958450-37-8 ]
  • [ 958450-39-0 ]
  • [ 958449-76-8 ]
  • [ 958449-77-9 ]
  • [ 958449-71-3 ]
  • [ 958449-78-0 ]
  • [ 958450-38-9 ]
  • [ 958449-69-9 ]
  • [ 958449-75-7 ]
  • [ 958449-70-2 ]
  • [ 958449-80-4 ]
YieldReaction ConditionsOperation in experiment
In 1,4-dioxane; at 70 - 80℃; for 12 - 48h;Combinatorial reaction / High throughput screening (HTS); Example 1. Preparation of a combinatorial library of substituted 2-aminomethyl-5-hydroxy-1H-indole-3-carboxylic acids esters of general formula 1.1. A mixture of 0.357 mmol of ester 2, 0.43 mmol of a secondary amine 3, and 0.43 mmol of formaldehyde in the form of formalin in 3 ml of dioxane is heated at 70-80°C at stirring for 12 to 48 hours. Progress of the reaction is monitored by chromato-mass-spectrometry. Upon completion of the reaction, the reaction mass is diluted with water, the residue is filtered and recrystallized from a suitable solvent, or purified by chromatography.
  • 2
  • [ 6457-49-4 ]
  • [ 4521-22-6 ]
  • C17H25NO2 [ No CAS ]
  • 3
  • [ 6457-49-4 ]
  • [ 67515-59-7 ]
  • [ 1260786-32-0 ]
YieldReaction ConditionsOperation in experiment
3.59 g With potassium carbonate; In dimethyl sulfoxide; at 100℃; for 4h; To a solution of piperidin-4-ylmethanol (2.19 g) in DMSO (40 mL) were added 4-fluoro-3- (trifluoromethyl) benzonitrile (3.00 g) and potassium carbonate (3.21 g) . The reactionmixture was stirred at 100C for 4 hr, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried overanhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (3.59 g) .XH NMR (300 MHz, DMSO-d6) delta 1.20-1.36 (2H, m) , 1.44-1.61 (1H, m) , 1.68-1.81 (2H, m) , 2.74-2.87 (2H, m) , 3.14-3.24 (2H, m) , 3.28-3.33 (2H, m) , 4.51 (1H, t, J = 5.3 Hz), 7.52 (1H, d, J = 8.5 Hz), 8.03 (1H, dd, J = 8.6, 2.0 Hz), 8.13 (1H, d, J = 1.9 Hz) .MS (ESI+) : [M+H]+.285.1.
  • 4
  • [ 6457-49-4 ]
  • [ 10241-97-1 ]
  • [ 1449664-31-6 ]
YieldReaction ConditionsOperation in experiment
73% With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In tetrahydrofuran; at 20℃; General procedure: To a solution of <strong>[10241-97-1]5-methyl-1H-indole-2-carboxylic acid</strong> (20) (263mg, 1.50mmol) in THF (7mL) were added 2-(piperidin-4-yl)ethanol (213mg, 1.65mmol), 1-hydroxybenzotriazole (HOBt, 101mg, 0.750mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDAC) hydrochloride (316mg, 1.65mmol), followed by stirring at room temperature for 14h. The reaction mixture was partitioned between ethyl acetate and 0.5M aqueous hydrochloric acid. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then concentrated in vacuo. The residue was recrystallized from ethyl acetate/acetonitrile (5mL/2mL) to give 3 (365mg, 85.0percent) as a beige powder.
  • 5
  • [ 6457-49-4 ]
  • [ 1199-49-1 ]
  • [ 1032823-75-8 ]
  • 6
  • [ 6457-49-4 ]
  • [ 22744-12-3 ]
  • methyl 4-(2-(4-formylpiperidin-1-yl)-2-oxoethyl)benzoate [ No CAS ]
  • 7
  • [ 6457-49-4 ]
  • [ 22744-12-3 ]
  • methyl 4-(2-(4-(hydroxymethyl)piperidin-1-yl)-2-oxoethyl)benzoate [ No CAS ]
YieldReaction ConditionsOperation in experiment
80% To a stirred solution of <strong>[22744-12-3]2-(4-(methoxycarbonyl)phenyl)acetic acid</strong> (1 g, 5.15mmol)and piperidin-4-ylmethanol (0.65 g, 5.67 mmol), in dichloromethane(25 mL) was added triethylamine (1..07 mL, 7.72mmol),the reaction was stirred at room temperature for lOmin, then cooled reaction mixture to 0C and added T3P (4.91 mL,7.72 mmol), and the resulting mixture was stirred at room temperature for 3 h.Reaction was monitored by TLC, after completion of reaction,the mixture was quenched with ice. The reaction mixture was diluted with water and extracted with dichloromethane (3x25 mL). The organic portion was washed with water, brine, dried over sodium sulphate and concentrated under reduced pressure to get the tiltle product as gummy solid. (XVI, 1.2 g, 80%). LC-MS m/z calcd for Ci6H2iN04, 291.1 ; found 292.1 [M+H]+.
  • 8
  • [ 6457-49-4 ]
  • [ 58656-98-7 ]
  • tert-butyl 4-(4-(hydroxymethyl)piperidin-1-yl)benzoate [ No CAS ]
YieldReaction ConditionsOperation in experiment
In dimethyl sulfoxide; at 120℃;Inert atmosphere; To a solution of <strong>[58656-98-7]ter<strong>[58656-98-7]t-butyl 4-fluorobenzoate</strong></strong> (23 g,0.12 mmol) in DM50 (100 mE) was added piperidin-4- ylmethanol (40.5 g, 0.35 mmol). The mixture was heated to 120 C. overnight under nitrogen. After cooling to room temperature, water (50 mE) was added to the reaction mixture, and extracted with ethyl acetate (20 mEx3). The organic layer was washed with brine (15 mEx3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated in vacuo, and purified by CC (PEEA=10: 1) to give compound tert-butyl 4-(4-(hydroxym- ethyl)piperidin-1 -yl)benzoate (31 g, 91.2%) as a white solid. ECMS (Agilent ECMS 1200-6120, Column:Waters X-l3ridge C18 (50 mmx4.6 mmx3.5 jim); Column Temperature: 40 C.; Flow Rate: 2.0 mE/mm; Mobile Phase:from 90% [(total 10mM AcONH4) waterCH3CN=900100 (vv)] and 10% [(total 10 mM AcONH4) water CH3CN=100900 (vv)] to 10% [(total 10 mM AcONH4) waterCH3CN=900100 (vv)] and 90% [(total 10 mM AcONH4) waterCH3CN=100900 (vv)] in 1.6 mm, then under this condition for 2.4 mm, finally changed to 90% [(total 10 mM AcONH4) waterCH3CN=900100 (vv)] and 10% [(total 10 mMAcONH4) waterCH3CN=100900 (vv)] in 0.1 mm and under this condition for 0.7 mm). Purity is 99.57%, Rt=2.035 mm.; MS Calcd.: 291.2; MS Found:292.2 [M+H]+. HPEC (Agilent HPEC 1200, Colunm: Waters X-l3ridge C18 (150 mmx4.6 mmx3.5 jim); Column Temperature: 40 C.; Flow Rate: 1.0 mE/mm; Mobile Phase:from 95% [water+10 mM NH4HCO3] and 5% [CH3CN] to 0% [water+10 mM NH4HCO3] and 100% [CH3CN] in 10 mm, then under this condition for 5 mi finally changed to 95% [water+10 mM NH4HCO3] and 5% [CH3CN] in 0.1mm and under this condition for 5 mi. Purity is 93 .27%,Rt=9.542 mm. ?H NMR (400 MHz, CDC13) oe 1.29-1.40 (2H, m),1.49 (1H, d, J=5.4 Hz), 1.57 (9H, s), 1.70-1.75 (1H, m), 1.82(2H, d, J=12.8 Hz), 2.80-2.87 (2H, m), 3.53 (2H, t, J=5.8Hz), 3.87-3.90 (2H, m), 6.85 (2H, d, J=9.2 Hz), 7.84 (2H, d,J=9.2 Hz). Chemical Formula: C,7H25N03, MolecularWeight: 291.39. Total H count from HNMR data: 25.
  • 9
  • [ 6457-49-4 ]
  • [ 13790-39-1 ]
  • (1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl)methanol [ No CAS ]
YieldReaction ConditionsOperation in experiment
81% With potassium carbonate; In acetonitrile; at 80℃; for 16h; To a stirred solution of <strong>[13790-39-1]4-chloro-6,7-dimethoxyquinazoline</strong> (1.00 g, 4.452 mmol, 1.00 equiv) in acetonitrile (40 mL) were added (piperidin-4-yl)methanol (0.77 g, 6.677 mmol, 1.50 equiv) and potassium carbonate (1.23 g, 8.903 mmol, 2.00 equiv). After stirring at 80C for 16 h, the reaction mixture was concentrated under vacuum to remove the solvent. The residue was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM/MeOH (20:1)) to afford 1.10 g (81%) of (l-(6,7-dimethoxyquinazolin-4- yl)piperidin-4-yl)m ethanol as an off-white solid.
  • 10
  • [ 6457-49-4 ]
  • [ 1340506-55-9 ]
  • C15H23N3O3 [ No CAS ]
YieldReaction ConditionsOperation in experiment
70% With tetra-(n-butyl)ammonium iodide; potassium carbonate; In 1,4-dioxane; at 100.0℃; for 1.0h; Combine <strong>[1340506-55-9]tert-butyl 6-chloropyridazine-3-carboxylate</strong> (7b) (0.5g, 2.0mmol), 4-hydroxymethylpiperidine (0.3g, 2.0mmol),Potassium carbonate (0.6g, 6mmol) and tetrabutylammonium iodide (0.08g, 0.2mmol) were added to 10mL 1,4-dioxane,Heat to 100 degrees. After stirring for 1 h, it was cooled to room temperature, the solvent was removed under reduced pressure, and 20 mL DCM and 20 mL water were added for extraction.After the organic layer was concentrated under reduced pressure, the residue was slurried with 30 mL of a mixed solution of dichloromethane/petroleum ether (v/v) = 1/2 for 20 minutes,After filtration, tert-butyl 6-[4-(hydroxymethyl)-1-piperidinyl]pyridazine-3-carboxylate (7c) (0.5 g, yield: 70%) was obtained.
 

Historical Records

Technical Information

Categories

Related Functional Groups of
[ 6457-49-4 ]

Alcohols

Chemical Structure| 297172-16-8

A115570 [297172-16-8]

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Related Parent Nucleus of
[ 6457-49-4 ]

Piperidines

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3-(Piperidin-4-yl)propan-1-ol

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