| Identification | Back Directory | [Name]
CHIR-090 | [CAS]
728865-23-4 | [Synonyms]
CS-2285
CHIR-090
CHIR-090 (CHIR 090
N-[(1S,2R)-2-Hydroxy-1-[(hydroxyamino)carbonyl]propyl]-4-[[4-(4-morpholinylmethyl)phenyl]ethynyl]benzamide
N-[(2S,3R)-3-hydroxy-1-(hydroxyamino)-1-oxobutan-2-yl]-4-[2-[4-(morpholin-4-ylmethyl)phenyl]ethynyl]benzamide
Benzamide, N-[(1S,2R)-2-hydroxy-1-[(hydroxyamino)carbonyl]propyl]-4-[2-[4-(4-morpholinylmethyl)phenyl]ethynyl]-
N-[(2S,3R)-3-hydroxy-1-(hydroxyamino)-1-oxobutan-2-yl]-4-[2-[4-(morphChemicalbookolin-4-ylmethyl)phenyl]ethynyl]benzamide | [Molecular Formula]
C24H27N3O5 | [MDL Number]
MFCD22665727 | [MOL File]
728865-23-4.mol | [Molecular Weight]
437.488 |
| Chemical Properties | Back Directory | [Description]
CHIR-090 is the first reported compound that in fact kills both E. coli and Pseudomonas aeruginosa in bacterial disk diffusion assays (Liang et al. 2011). Nonetheless, CHIR-090 was about 600-fold less effective against LpxC orthologs from the Rhizobiaceae family than against E. coli LpxC. In this way, studies have shown that the removal of morpholine ring, based on a chemical scaffold of reduced radius, was able to increase affinity by 20-fold for LpxC enzymes from the Rhizobiaceae family of bacteria and enhance the antibiotic activity against E. coli and P. aeruginosa by 2–4 fold over CHIR-090. | [density ]
1.33±0.1 g/cm3(Predicted) | [storage temp. ]
Store at -20°C | [solubility ]
≥21.85 mg/mL in DMSO; insoluble in EtOH; insoluble in H2O | [form ]
solid | [pka]
9.11±0.40(Predicted) | [color ]
White to off-white | [InChIKey]
FQYBTYFKOHPWQT-VGSWGCGISA-N | [SMILES]
C[C@H]([C@@H](C(NO)=O)NC(C1=CC=C(C=C1)C#CC2=CC=C(C=C2)CN3CCOCC3)=O)O |
| Hazard Information | Back Directory | [Uses]
CHIR-090 is a potent, slow, tight-binding inhibitor of the LpxC deacetylase. It binds to E. coli LpxC with a Ki of 4.0 nM. CHIR-090 is a click chemistry reagent, it contains an Alkyne group and can undergo copper-catalyzed azide-alkyne cycloaddition (CuAAc) with molecules containing Azide groups. | [Definition]
ChEBI: CHIR-090 is an L-threonine derivative obtained by formal condensation of the carboxy group of 4-({4-[(morpholin-4-yl)methyl]phenyl}ethynyl)benzoic acid with the amino group of N-hydroxy-L-threoninamide. It has a role as an antimicrobial agent, a lipopolysaccharide biosynthesis inhibitor and an EC 3.5.1.108 (UDP-3-O-acyl-N-acetylglucosamine deacetylase) inhibitor. It is an acetylenic compound, a member of morpholines, a member of benzamides, a L-threonine derivative and a hydroxamic acid. | [Synthesis]
General procedure for the synthesis of N-((2S,3R)-3-hydroxy-1-(hydroxyamino)-1-oxobutan-2-yl)-4-((4-(morpholinomethyl)phenyl)ethynyl)benzamide from CHIR090-Intermediate 1: To a stirred anhydrous methanol (5 mL) of hydroxylamine hydrochloride (400 mg, 5.76 mmol) at 0 °C and under nitrogen protection solution was slowly added sodium methanol (25 wt% methanol solution, 1.860 g, 8.60 mmol). After the reaction mixture was stirred at 0 °C for 20 min, a 1:1 methanol/THF (6 mL) solution of methyl ester 4 (829 mg, 1.90 mmol) was added. Subsequently, the reaction mixture was continued to be stirred at 0°C for 1 hr and then brought to room temperature and stirred for 4 hr. Upon completion of the reaction, the reaction was quenched with 1.0 M hydrochloric acid (6 mL), the organic solvent was removed by concentration by rotary evaporation, and the residue was diluted with DMSO (4 mL). Analytical reversed-phase high-performance liquid chromatography (RP-HPLC, C18 column, acetonitrile gradient 5-35% with 0.1% trifluoroacetic acid, UV detection wavelength 300 nm, run time 16 min) showed a purity of 85% for the crude product mixture. Purification of the crude product by preparative RP-HPLC and lyophilization of the collected fractions gave the target compound 5 (701 mg, 81% yield) as a fluffy white solid. Low resolution mass spectrometry (ESI+) m/z 438.1 (calculated value of 438.20 for C24H27N3O5+H); reversed-phase high-performance liquid chromatography (300 nm, 16-minute run time) retention time was 8.7 minutes. | [in vivo]
CHIR-090 is a potent antibiotic against E. coli and inhibits E. coli LpxC activity in vitro in the low nM range. E. coli W3110 colonies resistant to 1 μg/mL CHIR-090 are not observed without prior chemical mutagenesis. A strain of E. coli W3110 is able to grow on LB agar plates containing 1 to 10 μg/mL CHIR-090, which is 4 to 40 times above the MIC of 0.25 μg/mL under our conditions for wild-type E. coli W3110. The doubling time of W3110RL is 40 min in the presence of 1 μg/mL CHIR-090, which is exactly the same rate as wild-type in the absence of inhibitor. Wild-type cells stopped growing after about 2 h in the presence of 1 μg/mL CHIR-090[1]. | [target]
LpxC | [References]
[1] Barb AW, et al. Inhibition of lipid A biosynthesis as the primary mechanism of CHIR-090 antibiotic activity in Escherichia coli. Biochemistry. 2007 Mar 27;46(12):3793-802. DOI:10.1021/bi6025165
[2] Barb AW, et al. Structure of the deacetylase LpxC bound to the antibiotic CHIR-090: Time-dependent inhibition and specificity in ligand binding. Proc Natl Acad Sci U S A. 2007 Nov 20;104(47):18433-8. DOI:10.1073/pnas.0709412104
[3] Tan JH, et al. In Vitro and In Vivo Efficacy of an LpxC Inhibitor, CHIR-090, Alone or Combined with Colistin against Pseudomonas aeruginosa Biofilm. Antimicrob Agents Chemother. 2017 Jun 27;61(7). pii: e02223-16. DOI:10.1128/AAC.02223-16 |
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