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Structure of 346-55-4

Chemical Structure| 346-55-4

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Product Citations

Product Citations

Kitel, Radoslaw ; Surmiak, Ewa ; Borggrafe, Jan ; Kalinowska-Tluscik, Justyna ; Golik, Przemyslaw ; Czub, Miroslawa , et al.

Abstract: Here, we report the fragment-based drug discovery of potent and selective fragments that disrupt the Spire2-FMN2 but not the Spire1-FMN2 interaction. Hit fragments were identified in a differential scanning fluorimetry-based screen of an inhouse library of 755 compounds and subsequently validated in multiple orthogonal biophys. assays, including fluorescence polarization, microscale thermophoresis, and 1H-15N HSQC NMR. Extensive structure-activity relationships combined with mol. docking followed by chem. optimization led to the discovery of compound 13, which exhibits micromolar potency and high ligand efficiency (LE = 0.38). Therefore, this fragment represents a validated starting point for the future development of selective chem. probes targeting the Spire2-FMN2 interaction.

Alternative Products

Product Details of [ 346-55-4 ]

CAS No. :346-55-4
Formula : C10H5ClF3N
M.W : 231.60
SMILES Code : FC(C1=CC=C2C(Cl)=CC=NC2=C1)(F)F
MDL No. :MFCD00006775
InChI Key :LLRQVSZVVAKRJA-UHFFFAOYSA-N
Pubchem ID :67668

Safety of [ 346-55-4 ]

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

Computational Chemistry of [ 346-55-4 ] Show Less

Physicochemical Properties

Num. heavy atoms 15
Num. arom. heavy atoms 10
Fraction Csp3 0.1
Num. rotatable bonds 1
Num. H-bond acceptors 4.0
Num. H-bond donors 0.0
Molar Refractivity 51.76
TPSA ?

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

12.89 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

2.28
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

3.03
Log Po/w (WLOGP)?

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

5.06
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.

3.39
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

4.04
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

3.56

Water Solubility

Log S (ESOL):?

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

-3.61
Solubility 0.0566 mg/ml ; 0.000244 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.

-2.97
Solubility 0.25 mg/ml ; 0.00108 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

-5.21
Solubility 0.00143 mg/ml ; 0.00000617 mol/l
Class?

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

Moderately 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

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.

-5.56 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)

1.48

Application In Synthesis of [ 346-55-4 ]

* 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 [ 346-55-4 ]

[ 346-55-4 ] Synthesis Path-Downstream   1~3

  • 1
  • [ 346-55-4 ]
  • [ 6274-22-2 ]
  • [ 64100-39-6 ]
YieldReaction ConditionsOperation in experiment
With hydrogenchloride; In ethanol; EXAMPLE 6 p-[(7-trifluoromethyl-4-quinolyl)amino]-N-methylbenzamide hydrochloride A mixture of 0.1 mole of <strong>[6274-22-2]N-methyl-p-aminobenzamide</strong>, 0.1 mole of 4-chloro-7-trifluoromethylquinoline, 10 ml. of concentrated hydrochloric acid and 500 ml. of absolute ethanol is stirred at about 25 C. for 30 minutes. A precipitate begins to form, and the mixture is then heated at reflux for 4 hours. The mixture is cooled and filtered to obtain p-[(7-trifluoromethyl-4-quinolyl)amino]-N-methylbenzamide hydrochloride.
  • 2
  • [ 346-55-4 ]
  • [ 35613-44-6 ]
  • [ 25560-46-7 ]
YieldReaction ConditionsOperation in experiment
In acetonitrile; for 18h;Heating / reflux; A mixture of 7.2 g of 4-chloro-7-trifluoromethylquinoline, 5.4 g of methyl 2- aminophenylacetate and 250 mL of acetonitrile is heated under reflux for 18 hours. The solvent is evaporated under reduced pressure and the residue extracted 3 times with 200 mL portions of hot water. The aqueous extract is rendered basic with 10% ammonium hydroxide whereupon the desired compound precipitated; it was recrystallized from aqueous ethanol yielding colorless needles with a melting point of 140-1410C.
  • 3
  • [ 346-55-4 ]
  • [ 526-08-9 ]
  • [ 1489236-23-8 ]
YieldReaction ConditionsOperation in experiment
76% In N,N-dimethyl-formamide; for 12.0h;Reflux; General procedure: A mixture of 1 (2.31 g, 0.01 mol) and the corresponding sulfadrugs (0.012 mol) in dry DMF (20 mL) was refluxed for 12 h. The solid obtained after concentration was filtered and crystallized from dioxane to give 2-14, respectively.
 

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Technical Information

Categories

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