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Chemical Structure| 4152-90-3 Chemical Structure| 4152-90-3

Structure of 4152-90-3

Chemical Structure| 4152-90-3

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Product Citations

Product Citations

Dube, Phelelisiwe S. ; Legoabe, Lesetja J. ; Jordaan, Audrey ; Sigauke, Lester ; Warner, Digby F. ; Beteck, Richard M.

Abstract: Mycobacterium tuberculosis (Mtb) has an impermeable cell wall which gives it an inherent ability to resist many antibiotics. DprE1, an essential enzyme in Mtb cell wall synthesis, has been validated as a target for several TB drug candidates. The most potent and developmentally advanced DprE1 inhibitor, PBTZ169, is still undergoing clin. development. With high attrition rate, there is need to populate the development pipeline. Using a scaffold hopping strategy, we imprinted the benzenoid ring of PBTZ169 onto a quinolone nucleus. Twenty-two compounds were synthesized and screened for activity against Mtb, with six compounds exhibiting sub micromolar activity of MIC90 <0.244 μM. Compound 25 further demonstrated sub-micromolar activity when evaluated against wild-type and fluoroquinolone-resistant Mtb strains. This compound maintained its sub-micromolar activity against a DprE1 P116S mutant strain but showed a significant reduction in activity when tested against the DprE1 C387S mutant.

Keywords: DprE1 ; Quinolone ; Nitro compounds ; Mycobacterium tuberculosis ; Benzothiazinone

Purchased from AmBeed: ; ; ; ; ; ; ; ;

Alternative Products

Product Details of [ 4152-90-3 ]

CAS No. :4152-90-3
Formula : C7H8ClN
M.W : 141.60
SMILES Code : NCC1=CC=CC(Cl)=C1
MDL No. :MFCD00040752
InChI Key :BJFPYGGTDAYECS-UHFFFAOYSA-N
Pubchem ID :77802

Safety of [ 4152-90-3 ]

GHS Pictogram:
Signal Word:Danger
Hazard Statements:H314
Precautionary Statements:P501-P264-P280-P303+P361+P353-P301+P330+P331-P363-P304+P340+P310-P305+P351+P338+P310-P405
Class:8
UN#:2735
Packing Group:

Computational Chemistry of [ 4152-90-3 ] Show Less

Physicochemical Properties

Num. heavy atoms 9
Num. arom. heavy atoms 6
Fraction Csp3 0.14
Num. rotatable bonds 1
Num. H-bond acceptors 1.0
Num. H-bond donors 1.0
Molar Refractivity 39.13
TPSA ?

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

26.02 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

1.87
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

1.68
Log Po/w (WLOGP)?

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

1.65
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.

2.14
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

2.1
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

1.89

Water Solubility

Log S (ESOL):?

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

-2.2
Solubility 0.886 mg/ml ; 0.00626 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.

-1.84
Solubility 2.04 mg/ml ; 0.0144 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

-3.03
Solubility 0.131 mg/ml ; 0.000927 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

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.

-5.97 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

2.0
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 [ 4152-90-3 ]

* 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 [ 4152-90-3 ]

[ 4152-90-3 ] Synthesis Path-Downstream   1~9

  • 1
  • [ 4152-90-3 ]
  • [ 16097-62-4 ]
  • 2-(3-chloro-benzylamino)-6-trifluoromethyl-pyrimidin-4-ol [ No CAS ]
  • 2
  • [ 479691-42-4 ]
  • [ 4152-90-3 ]
  • [ 479691-64-0 ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate; In ethanol; hexane; ethyl acetate; Example 4 Preparation of Intermediate 4-[4-(3-Chloro-benzylamino)-pyrimidin-2-yl]-piperazine-1-carboxylic Acid Tert-Butyl Ester (I-4a): A mixture of <strong>[479691-42-4]4-(4-chloro-pyrimidin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester</strong> I-2a (100 mg, 0.33 mmol), 3-chlorobenzylamine (0.65 mL, 5.3 mmol) and potassium carbonate (71 mg, 0.67 mmol) in ethanol (5 mL) was heated at reflux for 24 h. The reaction mixture was cooled to room temperature, poured into H2O (15 mL) and extracted with EtOAc (2*18 mL). The combined organic extracts were washed with H2O (2*10 mL), brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by chromatography using 40% EtOAc in hexane as an eluding solvent to afford the title compound I-4a (93 mg) as a colorless oil. 1H NMR (400 MHz, CD3OD) delta 7.69 (d, 1H); 7.32 (s, 1H); 7.28-7.19 (m, 3H); 5.88 (d, 1H); 4.49 (s, 2H); 3.64-3.61 (m, 4H); 3.37-3.29 (m, 4H); 1.45 (s, 9H). MS (ES+) Calc: 403.2, Found: 404.0 (M+1).
  • 3
  • [ 4795-29-3 ]
  • [ 7154-73-6 ]
  • [ 2038-03-1 ]
  • [ 4572-03-6 ]
  • [ 27757-85-3 ]
  • [ 109-12-6 ]
  • [ 3731-53-1 ]
  • [ 107-10-8 ]
  • [ 7663-77-6 ]
  • [ 6628-04-2 ]
  • [ 2620-50-0 ]
  • polystyrene carboxaldehyde resin [ No CAS ]
  • [ 5071-96-5 ]
  • [ 617-89-0 ]
  • [ 28466-26-4 ]
  • [ 42185-03-5 ]
  • [ 453-71-4 ]
  • [ 19293-58-4 ]
  • [ 75-04-7 ]
  • [ 62-53-3 ]
  • [ 1003-03-8 ]
  • [ 51387-90-7 ]
  • [ 74-89-5 ]
  • [ 100-46-9 ]
  • [ 4152-90-3 ]
  • [ 68-41-7 ]
  • C9H8FN2O3Pol [ No CAS ]
  • C10H10FN2O3Pol [ No CAS ]
  • C11H12FN2O3Pol [ No CAS ]
  • C14H10FN2O3Pol [ No CAS ]
  • C11H8FN4O3Pol [ No CAS ]
  • C12H8FN4O3Pol [ No CAS ]
  • C13H10FN2O4Pol [ No CAS ]
  • C15H12FN2O3Pol [ No CAS ]
  • C14H11FN3O3Pol [ No CAS ]
  • C13H14FN2O3Pol [ No CAS ]
  • C13H10FN2O3PolS [ No CAS ]
  • C13H16FN2O4Pol [ No CAS ]
  • C13H14FN2O4Pol [ No CAS ]
  • C16H14FN2O4Pol [ No CAS ]
  • C11H9FN3O5Pol [ No CAS ]
  • C15H11ClFN2O3Pol [ No CAS ]
  • C17H17FN3O3Pol [ No CAS ]
  • C14H17FN3O3Pol [ No CAS ]
  • C14H17FN3O4Pol [ No CAS ]
  • C15H19FN3O3Pol [ No CAS ]
  • C16H12FN2O5Pol [ No CAS ]
  • C18H13FN3O3Pol [ No CAS ]
  • C15H17FN3O4Pol [ No CAS ]
  • C16H22FN4O3Pol [ No CAS ]
YieldReaction ConditionsOperation in experiment
A library of compounds in which R4 was various groups having the formula [CONHR »] was prepared by the process described above using 4-fluoro-3-nitrobenzoic acid, as follows: [72] Aldehyde resin was mixed with a primary amine (R17-NH2) in [DICHLOROETHANE] (DCE), triethylorthoformate (TEOF), and DMF (containing [1%] acetic acid) in a 1: 1: 1 ratio. After shaken overnight, sodium triacetoxyborohydride (20 eq. ) dissolved in DMF was added (Abdel-Magid, A. F. , et al., Tetrahedron Lett, 3 1: 5595-5598 (1990) ). After the mixture was shaken at room temperature overnight, the resin was filtered and washed with DMF (3 x 5 mL), [MEOH] [(3 X 5] mL), DMF [(3 X 5] mL), [MEOH] [(3 X 5] mL), and [CH2CL2] [(3 X 5] mL). The resin was washed twice with 5 mL DMF containing [1%] Hunig's base. To the filtered resin was added a mixture of 4-fluoro-3-nitrobenzoic acid (FNBA, 10 eq. ) and diisopropylcarbodiimide (DIC, 5 eq. ) in 2: 1 DMF : DCM. After shaking at room temperature overnight, the resin was filtered and washed with DMF (3 x 5 mL) and [CH2C12] (3 x 5 mL). [73] The resin was shaken with a primary amine [(R2-NH2)] in DMF for 8 hrs, filtered, and washed with DMF (6 x 5 mL), [MEOH] [(3 X 5] mL), and CH2C12 (3 x 5 mL). The aryl nitro group was reduced by the addition of tin (II) chloride dihydrate (20 eq. , >2 M) and N-methyl morpholine (NMM, 20 eq. ) in N-methyl pyrrolidinone (NMP). After shaken at room temperature overnight, the resin was filtered and washed with NMP (3 x 5 mL), [MEOH] (3 x 5 mL), and [CH2CI2 (3 X 5] mL). The resulting resin was shaken at room temperature with cyanogen bromide (5 eq. ) overnight, filtered, and washed with CH2Cl2 (3 x 5 mL), [MEOH] (3 x 5 mL), and CH2CI2 (3 x 5 mL). To produce a free amine, the resin was shaken for 30 min. in CHCl2 with the addition of sodium methoxide in methanol, filtered, and washed with CH2Cl2 [(4 X 5] mL). [[74]] In the final diversification step, the resin was heated at 500 C in DMF with a mono- substituted epoxide [[RLCH (-CH2O-)].] After shaking for 2 to 4 days the resin was filtered and washed with DMF (5 x 5 mL), [MEOH] [(3 X 5] mL), and CH2Cl2 (3 x 5 mL). T he resin-bound benzimidazole was cleaved from the solid-support by treatment with TFA: [CH2C12] (2: 3) for 1 hour at room temperature.
  • 4
  • [ 4152-90-3 ]
  • [ 231958-04-6 ]
  • [ 1387641-84-0 ]
YieldReaction ConditionsOperation in experiment
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃; for 1h;Inert atmosphere; To a stirred solution of <strong>[231958-04-6]3-tert-butoxycarbonylamino-4-methyl-benzoic acid</strong> (0.160 g, 0.64 mmol) in dichloromethane (5 mL) were added 1-hydroxybenzotriazole (0.172 g, 1.27 mmol) (Aldrich), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (0.244 g, 1.27 mmol) (Aldrich), triethyl amine (0.17 mL, 1.91 mmol) (Aldrich) and 3-chloro-benzylamine (0.07 mL, 1.00 mmol) (Aldrich) sequentially at room temperature under nitrogen and the resulting mixture was stirred for 1 hour (monitored by silica TLC; ethyl acetate-hexanes, 1:1). Solvent was distilled off under reduced pressure; obtained crude material was diluted with ice-water (10 mL) and was extracted with dichloromethane (3*25 mL). Collected organic parts were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude [5-(3-chloro-benzyl-carbamoyl)-2-methyl-phenyl]carbamic acid tert-butyl ester as off white solid, which was used for the next step reaction without further purification. (Yield 0.223 g, 93%).
  • 5
  • [ 1184-90-3 ]
  • [ 4152-90-3 ]
  • [ 1415910-60-9 ]
  • 6
  • [ 21279-62-9 ]
  • [ 4152-90-3 ]
  • 3-[(3-chlorobenzyl)amino]pyrazine-2-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
32% With triethylamine; In tetrahydrofuran; at 70℃; for 15.0h; General procedure: Compounds 1-6 were prepared according to conventional organic synthesis methods. 3-Chloropyrazine-2-carboxamide (1.27 mmol) was dissolved in THF (20 mL) in a round bottom flask and after that treated with two equivalents of the corresponding benzylamine and an equimolar amount of triethylamine. The reaction was conducted with continuous stirring and heating (70 C) under reflux in an oil bath for 15 h. Compounds 7-15 were synthesised using a microwave reactor with a focused field. 3-Chloropyrazine-2-carboxamide (1.27 mmol) was put into a thick-walled tube together with the corresponding benzylamine (2.54 mmol), pyridine (1.27 mmol), methanol (approx. 5 mL) and a magnetic stir bar and then sealed with a special cap. The reaction parameters were set according to the previously published paper as follows-140 C, 30 min, 200 W [29]. Reaction progress was checked by TLC (hexane:ethyl acetate-1:1). Regardless of the synthesis method used,all reaction mixtures were adsorbed on silica and subjected to preparative flash chromatography (hexane and ethyl acetate, gradient elution, detection wavelengths 260 nm and 280 nm). Products were recrystallized from ethanol or ethanol and water if necessary. All final substances were chemically characterized (1H-NMR, 13C-NMR, IR, melting point and elemental analysis).
  • 7
  • [ 30982-08-2 ]
  • [ 4152-90-3 ]
  • C17H18ClNO4 [ No CAS ]
  • 8
  • [ 479691-42-4 ]
  • [ 4152-90-3 ]
  • (3-chloro-benzyl)-(2-piperazin-1-yl-pyrimidin-4-yl)-amine, hydrochloride [ No CAS ]
  • 9
  • [ 4152-90-3 ]
  • [ 53554-29-3 ]
  • ethyl 2-((3-chlorobenzyl)amino)-4-hydroxypyrimidine-5-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
91.3% In ethanol; for 24h;Reflux; Sealed tube; General procedure: To a Radley reaction carousel tube, add 1 equivalent 1, 1.1 equivalents of the amine, a stir bar, and 5 mL 95% ethanol. Reflux while stirring for 24 hours. After cooling to room temperature the resulting precipitate was collected by vacuum filtration, washing with 10 mL deionized water and 5 mL chloroform.
 

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Technical Information

Categories

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[ 4152-90-3 ]

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