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Quality Control of [ 1123-93-9 ] Purity: 98% SDS Specification

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Product Citations

Novel amides of mycophenolic acid and some heterocyclic derivatives as immunosuppressive agents

Walczak, Juliusz Maksymilian ; Iwaszkiewicz-Grzes, Dorota ; Ziomkowska, Michalina ; Sliwka-Kaszynska, Magdalena ; Dasko, Mateusz ; Trzonkowski, Piotr , et al.

DOI: 10.1080/14756366.2022.2127701 PubMed ID: 36189734 J. Enzym. Inhib. Med. Ch.,2022,37(1):2725-2741.

Abstract: The group of 18 new amide derivatives of mycophenolic acid (MPA) and selected heterocyclic amines was synthesised as potential immunosuppressive agents functioning as inosine-5′-monophosphate dehydrogenase (IMPDH) uncompetitive inhibitors. The synthesis of 14 of them employed uronium-type activating system (TBTU/HOBt/DIPEA) while 4 of them concerned phosphonic acid anhydride method (T3P/Py) facilitating amides to be obtained in moderate to excellent yields without the need of phenolic group protection. Most of optimised protocols did not require complicated reaction work-ups, including chromatographic, solvent-consuming methods. The biological activity assay was performed on the T-Jurkat cell line and peripheral mononuclear blood cells (PBMCs) which are both dedicated for antiproliferative activity determination. Each of designed derivatives was characterised by reduced cytotoxicity and benzoxazole analogue (A2) revealed the most promising activity. Subsequently, an observed structure-activity relationship was discussed.

Keywords: Mycophenolic acid ; amide derivatives ; heterocycles ; benzoxazole ; IMPDH inhibition

Purchased from AmBeed: 934-32-7 ; 1477-42-5 ; 5464-79-9 ; 5464-79-9 ; 136-95-8 ; 95-24-9 ; 533-30-2 ; 1123-93-9 ; 6285-57-0 ; 15864-32-1 ; 29927-08-0 ; 348-40-3 ; 58-63-9 ; 4570-41-6 ; 75985-45-4 ; 24280-93-1 ; 2536-91-6 ; 19952-47-7 ; 1747-60-0 ; 777-12-8 ; 63837-12-7 ; 58-63-9

Product Details of [ 1123-93-9 ]

CAS No. :	1123-93-9
Formula :	C₇H₆N₂S
M.W :	150.20
SMILES Code :	NC1=CC=C(SC=N2)C2=C1
MDL No. :	MFCD04115282
InChI Key :	UJZYHMZRXGNDFB-UHFFFAOYSA-N
Pubchem ID :	70749

Safety of [ 1123-93-9 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302-H315-H319-H335
Precautionary Statements:	P261-P305+P351+P338

Computational Chemistry of [ 1123-93-9 ] Show Less

Physicochemical Properties

Num. heavy atoms	10
Num. arom. heavy atoms	9
Fraction Csp3	0.0
Num. rotatable bonds	0
Num. H-bond acceptors	1.0
Num. H-bond donors	1.0
Molar Refractivity	44.02
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	67.15 ?2

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.43
Log P_o/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry	1.33
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.89
Log P_o/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.	0.85
Log P_o/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	2.47
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.59

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.28
Solubility	0.797 mg/ml ; 0.00531 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.	-2.34
Solubility	0.684 mg/ml ; 0.00456 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	-2.59
Solubility	0.384 mg/ml ; 0.00256 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.	-6.27 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)	1.92

Application In Synthesis of [ 1123-93-9 ]

* 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 [ 1123-93-9 ]

[ 1123-93-9 ] Synthesis Path-Downstream 1~32

1
[ 2942-07-6 ]
[ 1123-93-9 ]

Yield	Reaction Conditions	Operation in experiment
52%		A mixture OF 5-NITRO-1, 3-benzothiazole (Description 5,1. 9 g, 11 mmol) and tin (II) chloride dihydrate (8.6 g, 38 mmol) in 2-propanol (30 ml) was heated to reflux for 24 h. The cooled reaction mixture was poured onto an ice/water mixture (85 ml) and adjusted to pH7 with sodium hydroxide (s). The mixture was extracted with ethyl acetate (3 X 50 ml) and the combined organic layers were dried over sodium sulfate, filtered and evaporated. The residue was purified by column chromatography on silica (eluant 1 : 1 hexane: ethyl acetate) to give 1, 3-benzothiazol-5-amine (820 mg, 52 %). LHNMR (CDCL3) 6 6.85 (1H, dd, J2. 3,8. 6), 7.40 (1H, d, J2. 1), 7.66 (1H, d, J 8.4), 8.90 (1H, s).
	With stannous chloride;	5-Aminobenzothiazole To a solution of SnCl2 (7.0 g, 8.8 mmol) and 14 mL of con.HCl was added 5-nitrobenzothiazole (0.65 g, 3.6 mmol) in a portion and resulting reaction mixture was stirred for 1 h at 25 C. The reaction mixture was basified with aqueous NaOH and extracted with EtOAc. Combined organic layers were dried over Na2 SO4 and concentrated in vacuo, yielding an oil (0.47 g, 3.2 mmol, 89%) which was identified as the amine (>95% pure) and subjected to the following reaction without further purification.
	With hydrogen;palladium 10% on activated carbon; In tetrahydrofuran; methanol;	Step 9.2: 5-Amino-benzothiazole Purified 5-nitro-benzothiazole (7.2 g, 0.04 mol, see WO 98/23612, example 7A), dissolved in 160 mL of methanol and 160 mL of THF, is hydrogenated in the presence of 1.6 g Pd/C (10%; Engelhard 4505). The catalyst is filtered off, the filtrate concentrated and the residual oil purified by flash chromatography on silica gel using dichloromethanol/methanol 97:3 as eluent. The title compound is obtained as a colorless solid: m.p. 76-78 C., HPLC tR=0.76 min; MS-ES+: (M+H)+=151; Rf (dichloromethane/methanol 97:3)=0.76.

	With hydrogen;10% palladium on activated carbon; In tetrahydrofuran; methanol;	Purified 5-nitro-benzothiazole (7.2 g, 0.04 mol, see WO 98/23612, example 7A), dissolved in 160 mL of methanol and 160 mL of THF, is hydrogenated in the presence of 1.6 g Pd/C (10 %; Engelhard 4505). The catalyst is filtered off, the filtrate concentrated and the residual oil purified by flash chromatography on silica gel using dichloromethanol/methanol 97:3 as eluent. The title compound is obtained as a colorless solid: m.p. 76-78 0C, HPLC tR = 0.76 min; MS-ES+: (M+H)+ = 151 ; Rf (dichloromethane/methanol 97:3) = 0.76.
		5-Nitrobenzo[d]thiazole (150 mg) was dissolved in THF (20 mL) at 0 0C and AcOH (1 mL) was added followed by Zinc dust (1.65 g). Mixture was stirred at RT for 1 h and was filtered on silica pad (rinsed with EtOAc). Solvent was evaporated, residue was diluted with NaHCO3 and extracted with EtOAc. Organic phases was dried, filtered and evaporated to give benzo[d]thiazol-5-amine.
2.1 g	With tin(II) chloride dihdyrate; In ethyl acetate;Reflux;	A mixture of 5-nitrobenzo[d]thiazole (3.0 g, 16.7 mmol) and SnCl2*2H2O (19 g, 84.2 mmol) in EtOAc (150 mL) was stirred at reflux overnight. The reaction mixture was basified with Et3N until pH 8 and the precipitate was filtered. The filtrate was concentrated in vacuo and the residue was purified by column chromatography on silica gel (EtOAc/DCM = 2:1) to afford the title compound as a yellow solids (2.1 g). 1H NMR (400 MHz, CDCl3): oe 8.92 (s, 1H), 7.69 (d, 1H), 7.41 (d, 1H), 6.86 (dd, 1H), 3.82 (brs, 2H); LCMS: 151 (M+H).

References: [1]Journal of Medicinal Chemistry,2017,vol. 60,p. 957 - 971.
[2]Catalysis Letters,2014,vol. 144,p. 1258 - 1267.
[3]Organic Letters,2019,vol. 21,p. 3764 - 3768.
[4]Patent: WO2005/28445,2005,A2 .Location in patent: Page/Page column 28.
[5]Yakugaku Zasshi/Journal of the Pharmaceutical Society of Japan,1942,vol. 62,p. 47,51; dtsch. Ref. S. 19, 22.
Chem.Abstr.,1951,p. 609.
[6]Helvetica Chimica Acta,1950,vol. 33,p. 1429,1431.
[7]Chemistry of Heterocyclic Compounds,1972,vol. 8,p. 36 - 38.
Khimiya Geterotsiklicheskikh Soedinenii,1972,vol. 8,p. 38 - 40.
[8]Patent: US5677321,1997,A .
[9]Patent: US2006/35897,2006,A1 .Location in patent: Page/Page column 23.
[10]Patent: WO2008/8821,2008,A2 .Location in patent: Page/Page column 42; 43.
[11]Patent: WO2007/48070,2007,A2 .Location in patent: Page/Page column 112.
[12]Phytochemistry,2012,vol. 74,p. 159 - 165.
[13]Patent: WO2013/142266,2013,A1 .Location in patent: Page/Page column 00506.

2
[ 1123-93-9 ]
[ 16463-38-0 ]
[ 149474-18-0 ]

References: [1]Tetrahedron Letters,1993,vol. 34,p. 2609 - 2612.

3
1-benzyl-1-methyl-4-oxopiperidin-1-ium iodide salt [ No CAS ]
[ 1123-93-9 ]
C₁₂H₁₂ON₂S [ No CAS ]

References: [1]Organic Letters,1999,vol. 1,p. 1261 - 1262.

4
[ 1123-93-9 ]
5<i>H</i>-1-thia-3,5,6-triaza-cyclopenta[<i>b</i>]anthracen-10-one [ No CAS ]

References: [1]Medicinal Chemistry Research,1995,vol. 5,p. 522 - 533.

5
[ 1123-93-9 ]
thiazolo[4,5-a]acridin-11(6H)-one [ No CAS ]

References: [1]Tetrahedron Letters,1993,vol. 34,p. 2609 - 2612.

6
[ 1123-93-9 ]
[ 211-37-0 ]