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Chemical Structure| 657408-07-6

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Lish, Matthew S ; McKeon, Jillian EM ; Palmentiero, Caroline M ; Pomeroy, Julia M ; Roster, Colm P ; Guzei, Ilia A , et al.

Abstract: Primary amoebic meningoencephalitis (PAM) is a human brain infection caused by Naegleria fowleri with a 97% mortality rate. Quinazolinones resulting from a Mannich-coupled domino rearrangement were recently identified as inhibitors of the amoeba. Herein, we resolved the effective concentrations for 25 pilot compounds and then, using the Mannich protocol and a key late-stage, N-demethylation/functionalization, we synthesized 53 additional analogs to improve potency, solubility and microsomal stability. We established an antiamoebic quinazolinone pharmacophore, culminating in (±)-trans-57b which featured the best combination of potency, selectivity index, solubility, and microsomal stability. Enantiomeric separation afforded (4aS,13bR)-57b (BDGR-20237) with a 41-fold potency advantage over its enantiomer. ADME and mouse pharmacokinetic profiling for BDGR-20237 revealed high brain penetrance but a limited half-life which did not statistically enhance the mouse survival in a pilot efficacy study. The pharmacophoric model, supported by 88 quinazolinones, several of which exhibit subnanomolar potency, will guide further scaffold optimization.

Purchased from AmBeed: ; ; ;

Gilbert, Robert ; Davis, Christopher W ; Bingham, Tanner W ; Sarlah, David ;

Abstract: A dearomative 1,4-hydroamination of nonactivated arenes has been developed, using a key arene-arenophile photocycloaddition strategy to disrupt aromaticity. Palladium catalysis with K-Selectride® as a hydride source uniquely enables selective reactivity and provides access to a range of substituted 1,4-cyclohexadienes from aromatic starting materials. We demonstrate a few synthetic applications of this scalable procedure by preparing highly-functionalized small molecules in three to four steps from naphthalene.

Keywords: Dearomatization ; Hydroamination ; Arenophiles ; Palladium ; Catalysis

Purchased from AmBeed: ; ; ; ;

Alternative Products

Product Details of [ 657408-07-6 ]

CAS No. :657408-07-6
Formula : C26H35O2P
M.W : 410.53
SMILES Code : C1(CCCCC1)P(C2=C(C=CC=C2)C3=C(C=CC=C3OC)OC)C4CCCCC4
MDL No. :MFCD05861611
InChI Key :VNFWTIYUKDMAOP-UHFFFAOYSA-N
Pubchem ID :11269872

Safety of [ 657408-07-6 ]

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

Computational Chemistry of [ 657408-07-6 ] Show Less

Physicochemical Properties

Num. heavy atoms 29
Num. arom. heavy atoms 12
Fraction Csp3 0.54
Num. rotatable bonds 6
Num. H-bond acceptors 2.0
Num. H-bond donors 0.0
Molar Refractivity 126.99
TPSA ?

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

32.05 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

4.6
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

6.68
Log Po/w (WLOGP)?

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

7.14
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.

5.28
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

7.31
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

6.2

Water Solubility

Log S (ESOL):?

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

-6.5
Solubility 0.000129 mg/ml ; 0.000000313 mol/l
Class?

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

Poorly soluble
Log S (Ali)?

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

-7.16
Solubility 0.0000287 mg/ml ; 0.0000000698 mol/l
Class?

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

Poorly 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

-8.06
Solubility 0.00000353 mg/ml ; 0.0000000086 mol/l
Class?

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

Poorly soluble

Pharmacokinetics

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)
and tested on 415 molecules (test set)
10-fold CV: ACC=0.72 / AUC=0.77
External: ACC=0.88 / AUC=0.94

Yes
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

Yes
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.

-4.06 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

1.0
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

1.0
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<2.0
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)

4.47

Application In Synthesis of [ 657408-07-6 ]

* 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 [ 657408-07-6 ]

[ 657408-07-6 ] Synthesis Path-Downstream   1~4

  • 1
  • [ 657408-07-6 ]
  • potassium phosphate [ No CAS ]
  • [ 1592-95-6 ]
  • [ 5408-56-0 ]
  • [ 1060735-14-9 ]
  • [ 1126522-69-7 ]
  • [ 865-48-5 ]
  • [ 1150-62-5 ]
YieldReaction ConditionsOperation in experiment
With N2;tris-(dibenzylideneacetone)dipalladium(0); Pd2(dba)3; In tetrahydrofuran; 5,5-dimethyl-1,3-cyclohexadiene; hexane; dichloromethane; toluene; A mixture of 9-phenyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-9H-carbazole (12 g, 32.5 mmol), 3-bromo-9H-carbazole (6.66 g, 27.1 mmol), and potassium phosphate (34.5 g, 162 mmol) in 500 mL of toluene and 50 mL of H2O was bubbled with N2 for 20 min. Dicyclohexyl(2',6'-dimethoxybiphenyl-2-yl)phosphine (0.445 g, 1.083 mmol) and Pd2(dba)3 (0.248 g, 0.271 mmol) were then added, and the mixture was heated to reflux under N2 for 5 h. TLC indicated the reaction was done. The reaction was extracted with dichloromethane and washed with brine and dried with magnesium sulfate. The solution was heated up to boil. Hexane was added. The dichloromethane was boiled off and hexanes volume reached about 1200 mL. Precipitate formed during boiling off dichloromethane. The solution was cooled to room temperature and stirred overnight. The precipitate was filtered and dissolved in THF and ran a short silica gel plug. After dried under vacuum at 60 C., 9.6 g (87%) of product was obtained. Synthesis of Compound 1. A mixture of <strong>[5408-56-0]2-iododibenzo[b,d]furan</strong> (2.59 g, 8.81 mmol), 9-phenyl-9H,9'H-3,3'-bicarbazole (3 g. 7.34 mmol), and sodium t-butoxide (1.764 g, 18.36 mmol) in 200 mL of xylene was bubbled with N2 for 20 min. Dicyclohexyl(2',6'-dimethoxybiphenyl-2-yl)phosphine (0.121 g, 0.294 mmol) and Pd2(dba)3 (0.067 g, 0.073 mmol) were then added, and the mixture was heated to reflux under N2 for 24 h. The mixture was cooled and filtered through Celite. After solvent evaporation, the residue was coated on Celite and purified by column chromatography 3.7 g of product was obtained after column.
  • 2
  • [ 657408-07-6 ]
  • [ 6287-82-7 ]
  • [ 22751-52-6 ]
  • [ 98-80-6 ]
  • [ 201-69-4 ]
YieldReaction ConditionsOperation in experiment
With potassium phosphate;tris-(dibenzylideneacetone)dipalladium(0); In dichloromethane; water; ethyl acetate; toluene; Example 4 Synthesis of Benzo[b]phenanthro[9,10-d]thiophene The synthesis is based on Tetrahedron, 37(1), 75-81, 1981. To a 500 mL 3-neck round bottom flask was added <strong>[6287-82-7]2,3-dibromobenzo[b]thiophene</strong> (5.0 g, 17.12 mmol), phenylboronic acid (5.2 g, 42.81 mmol), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (281 mg, 0.68 mmol), K3PO4 (11.8 g, 51.36 mmol), 150 mL of toluene and 5 mL of water. N2 was bubbled directly into the flask for 20 minutes. Pd2(dba)3 (157 mg, 0.171 mmol) was added to the reaction mixture which was then heated to reflux for 5 h. Water was added to the cooled reaction mixture and the layers were separated. The aqueous layer was extracted twice with CH2Cl2 and the organic extracts were dried over MgSO4, filtered, and evaporated to yield a red oil which was dried to give 5.71 g of a red solid. The solid was purified by silica gel column chromatography (10-20% CH2Cl2 in hexanes) to yield 4.81 g of the product as a white solid. A photoreactor was loaded with 2,3-diphenylbenzo[b]thiophene (4.81 g, 16.8 mmol) and 800 mL toluene. The solution was irradiated using a medium pressure mercury lamp for 12 h. The solvent was evaporated and the residue was purified by silica gel column chromatography (0-20% of EtOAc in hexanes). The product was collected and recrystallized from hexanes (with a small amount of EtOAc to initially dissolve the material) to yield 1.61 g of product an off-white solid. Benzo[b]phenanthro[9,10-d]thiophene showed a triplet energy of 488 nm at 77 Kin 2-methylTHF.
  • 3
  • [ 657408-07-6 ]
  • potassium phosphate [ No CAS ]
  • Pd2(bda)3 [ No CAS ]
  • [ 98-80-6 ]
  • 2-chlorobenzofuro[2,3-b]pyridine [ No CAS ]
  • [ 1221398-11-3 ]
YieldReaction ConditionsOperation in experiment
With nitrogen; In water; toluene; 2-chlorobenzofuro[2,3-b]pyridine (1.33 g, 6.53 mmol), phenylboronic acid (1.19 g, 9.80 mmol), potassium phosphate (4.51 g, 19.59 mmol), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (0.214 g, 0.522 mmol) and Pd2(bda)3 (0.119 g, 0.13 mmol) were to toluene (40 mL) and water (4 mL). Nitrogen was bubbled through the solution for 30 minutes and then the solution was refluxed for overnight in an atmosphere of nitrogen. The reaction was then allowed to cool to room temperature and the organic phase was separated from the aqueous phase. The aqueous phase was extracted with ethylacetate and the organic fractions were combined and dried over sodium sulfate and the solvent removed under vacuum. The product was chromatographed using silica gel with ethylacetate and hexanes as the eluent. The solvent was removed to give 1.45 g of title compound. Synthesis of Compound 8: Iridium intermediate (1.15 g, 1.55 mmol) and 2-phenylbenzofuro[2,3-b]pyridine (1.14 g, 4.66 mmol) was mixed in 30 mL of anhydrous ethanol.
  • 4
  • [ 657408-07-6 ]
  • [ 52522-40-4 ]
  • 3,5-bis(4-tert-butylphenyl)phenyl-1-boronic acid pinacol ester [ No CAS ]
  • [ 77-98-5 ]
  • [ 96042-30-7 ]
YieldReaction ConditionsOperation in experiment
In water; ethyl acetate; toluene; Stage 2: Stage 1 material (8.50 g) and 3,5-bis(4-tert-butylphenyl)phenyl-1-boronic acid pinacol ester (15.50 g) were dissolved in toluene (230 mL). The solution was purged with nitrogen for 1 h before 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (66 mg) and tris(dibenzylidene)dipalladium (75 mg) were added using 10 mL of nitrogen-purged toluene. A 20wtpercent solution of tetraethylammonium hydroxide in water (60 mL) was added in one portion and the mixture as stirred for 20 h with the heating bath set to 105 °C. T.L.C. analysis indicated all the stage material had been consumed and only one fluorescent spot was observed. The reaction mixture was cooled and filtered into a separating funnel. The layers were separated and the aqueous layer extracted with toluene. The organic extracts were washed with water, dried with magnesium sulphate, filtered and concentrated to yield the crude product as a yellow/orange solid. Pure compound was obtained by column chromatography eluting with a gradient of ethyl acetate in hexanes followed by precipitation from DCM/methanol. HPLC indicated a purity of 99.75percent and a yield of 80percent (11.32g). 1H NMR (referenced to CDCl3): 7.83 (3H, d), 7.76 (6H, s), 7.73 (3H, s) 7.63 (12H, d) 7.49 (12H, d), 7.21 (3H, dd), 6.88 (3H, d), 4.28 (9H, s), 2.25 (3H, m), 1.98 (3H, m), 1.4-1.5 (57H, m), 1.23 (3H, m), 0.74 (9H, t)
 

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