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Chemical Structure| 1003-29-8 Chemical Structure| 1003-29-8

Structure of Pyrrole-2-carboxaldehyde
CAS No.: 1003-29-8

Chemical Structure| 1003-29-8

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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 [ 1003-29-8 ]

CAS No. :1003-29-8
Formula : C5H5NO
M.W : 95.10
SMILES Code : O=CC1=CC=CN1
MDL No. :MFCD00005217
InChI Key :ZSKGQVFRTSEPJT-UHFFFAOYSA-N
Pubchem ID :13854

Safety of [ 1003-29-8 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H315-H319-H335
Precautionary Statements:P261-P305+P351+P338

Computational Chemistry of [ 1003-29-8 ] Show Less

Physicochemical Properties

Num. heavy atoms 7
Num. arom. heavy atoms 5
Fraction Csp3 0.0
Num. rotatable bonds 1
Num. H-bond acceptors 1.0
Num. H-bond donors 1.0
Molar Refractivity 26.18
TPSA ?

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

32.86 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

0.96
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

0.51
Log Po/w (WLOGP)?

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

0.83
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.

-0.56
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

1.61
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

0.67

Water Solubility

Log S (ESOL):?

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

-1.21
Solubility 5.82 mg/ml ; 0.0612 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.

-0.77
Solubility 16.1 mg/ml ; 0.17 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

-1.47
Solubility 3.24 mg/ml ; 0.034 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

Yes
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.

-6.52 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

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<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 [ 1003-29-8 ]

* 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 [ 1003-29-8 ]

[ 1003-29-8 ] Synthesis Path-Downstream   1~16

  • 1
  • [ 1003-29-8 ]
  • [ 58656-98-7 ]
  • 4-(2-Formyl-pyrrol-1-yl)-benzoic acid tert-butyl ester [ No CAS ]
  • 2
  • [ 1003-29-8 ]
  • [ 7089-68-1 ]
  • [ 1779-49-3 ]
  • [ 207505-40-6 ]
  • 3
  • [ 1003-29-8 ]
  • [ 766-36-9 ]
  • (Z)-5-((1H-pyrrol-2-yl)methylene)-3-ethyl-4-methyl-1H-pyrrol-2(5H)-one [ No CAS ]
  • 4
  • [ 1003-29-8 ]
  • [ 326-62-5 ]
  • (Z)-2-(2-fluorophenyl)-3-(1H-pyrrol-2-yl)acrylonitrile [ No CAS ]
  • 5
  • [ 1003-29-8 ]
  • [ 656-35-9 ]
  • 2-(2,4-difluoro-phenyl)-3-(1<i>H</i>-pyrrol-2-yl)-acrylonitrile [ No CAS ]
  • 6
  • [ 1003-29-8 ]
  • [ 75279-55-9 ]
  • 2-(2-chloro-6-fluoro-phenyl)-3-(1<i>H</i>-pyrrol-2-yl)-acrylonitrile [ No CAS ]
  • 7
  • [ 931-34-0 ]
  • [ 1003-29-8 ]
  • 8
  • [ 1003-29-8 ]
  • [ 99365-48-7 ]
  • [ 276251-73-1 ]
YieldReaction ConditionsOperation in experiment
96% With piperidine; In isopropyl alcohol; at 85℃; for 2h; A mixture of <strong>[99365-48-7]4-bromo-1,3-dihydro-2H-indol-2-one</strong> (0.2 g, 0.94 mmol) (see T. Kosuge et. al., Chem. Pharm. Bull. 33(4):1414-1418 (1985)), and excess pyrrole-2-carboxaldehyde (0.11 g, 1.13 mmol) (Aldrich) in 1% piperidine in 2-propanol (2 mL) was heated at 85 C for 2 h. Hot water (2 mL) was added. On cooling, the crystallized product was filtered off, washed with aqueous 2-propanol and dried. (Yield 0.26 g, 96%)
  • 9
  • [ 1003-29-8 ]
  • [ 20348-09-8 ]
  • [ 312973-06-1 ]
  • [ 312973-72-1 ]
YieldReaction ConditionsOperation in experiment
2%; 15% Sodium methoxide (0.65 g, 0.012 mol) was added in one portion to a mixture of 2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one (1.50 g, 0.01 mol) and pyrrole-2-carboxaldehyde (1.58 g, 0.016 mol) in dry DMF (10 ml). The reaction mixture was refluxed for 48 h, then cooled to room temperature, poured into crushed ice and left overnight at 4 C. The precipitated solid was filtered off, washed with water and dried. The dark solid was boiled with ethanol (150 ml) and filtered hot to remove impurities. The filtrate was evaporated to dryness under reduced pressure, and the residue was purified by silica gel chromatographed using (95:5) toluene:ethyl acetate as the mobile phase.
  • 10
  • [ 1003-29-8 ]
  • [ 942067-98-3 ]
  • [ 258827-90-6 ]
  • 12
  • [ 1003-29-8 ]
  • [ 1668-54-8 ]
  • [ 1465740-09-3 ]
  • 13
  • [ 1003-29-8 ]
  • [ 1120-95-2 ]
  • [ 1600527-79-4 ]
YieldReaction ConditionsOperation in experiment
34% With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 20h; General procedure: A flask was charged with 2-formylpyrrole 1 (5.00 g, 52.6 mmol), K2CO3 (8.72 g, 63.1 mmol), 2-fluoropyridine 2 (9.0 mL, 105.2 mmol) and DMF (26 mL).The mixture was heated at 100 °C for 20 h and then cooled to rt. The reaction mixturewas diluted with water, extracted with MTBE, and the organic phase was dried (MgSO4), filtered, and concentrated. The crude product was purified by chromatography on SiO2(hexanes/EtOAc, 95:5 to 85:15 v/v) to give the product 3 (5.71 g, 63percent) as a tan solid.
  • 14
  • [ 1003-29-8 ]
  • [ 14704-31-5 ]
  • 1-([1,1'-biphenyl]-3-ylmethyl)-1H-pyrrole-2-carbaldehyde [ No CAS ]
YieldReaction ConditionsOperation in experiment
98% With tetrabutylammomium bromide; sodium hydroxide; In dichloromethane; water; at 0 - 20℃; To a stirred mixture of 1H-pyrrole-2-carbaldehyde 39 (200 mg, 2.10 mmol), TBAB (68 mg, 0.21 mmol) and <strong>[14704-31-5]3-(bromomethyl)-1,1'-biphenyl</strong> 38 (624 mg, 2.52 mmol ) in DCM was added aqueous NaOH solution (1.2 mL, 1.25 M in H2O) dropwise over a period of 30 min at 0 C. Then the mixture was allowed to warm to room temperature. After stirring overnight, the mixture was diluted with water, and extracted with DCM (3 x 30 mL). The combined organic phases were washed with 2 M HCl, saturated NaHCO3 and brine, dried with Na2SO4, filtered, concentrated and purified by silica gel chromatography to afford 43 (540 mg, 98%) as a white solid.
  • 15
  • [ 1003-29-8 ]
  • [ 78364-55-3 ]
  • 6-fluoro-2-[2-((1H-pyrrol-2-yl)methylene)hydrazino]benzothiazole [ No CAS ]
YieldReaction ConditionsOperation in experiment
79% With acetic acid; In ethanol; at 80℃; for 0.166667h;Microwave irradiation; General procedure: 2-(2-Arylidenehydrazino)-6-fluorobenzothiazoles 6a-r. General Procedure D. A mixture of compound 2 (0.0549 g, 0.0003 mol), the appropriate aromatic aldehyde (0.00033 mol) and glacial acetic acid (0.1 mL) in ethanol (5 mL) was heated under microwave (20 W) at 80 °C for 10 min. On cooling, the precipitated solid was collected by filtration, washed with water, dried and crystallized from the appropriate solvent to give the desired compounds 6a-r.
  • 16
  • [ 1003-29-8 ]
  • [ 53137-27-2 ]
  • [ 931-53-3 ]
  • [ 106-49-0 ]
  • N-(2-(cyclohexylamino)-2-oxo-1-(1H-pyrrol-2-yl)ethyl)-2,4-dimethyl-N-(p-tolyl)thiazole-5-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
35% General procedure: The aldehyde (0.8 equivalent) and amine (0.7 equivalent) were dissolved in methanol (2.0 mL) and stirred for two to 3 h depending upon the starting material. The acid (100 mg, 1 equivalent) and isocyanide (0.7 equivalent) were added in the reaction mixture and further stirred. The reaction mixture was monitored using TLC analysis.Water (4 mL) was added upon completion of the reaction.The resulted solid was filtered off and dissolved in ethyl acetate(10 mL), washed with water (2 3 mL) and dried over sodium sulphate. The crude product was purified using silica gel column chromatography. The ethyl acetate:hexane (6:4) solvent system was used for the purification of these compounds.
 

Historical Records

Technical Information

Categories

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