CHIR-090


Catalog No. size PriceQuantity
M6531-2 2mg solid $144
M6531-10 10mg solid $570

Description

Cas:728865-23-4

Product Information:

CHIR-090 is a very potent and selective LpxC inhibitor. CHIR-090 has excellent antibiotic activity against Pseudomonas aeruginosa and Escherichia coli. CHIR-090 is also a two-step slow, tight-binding inhibitor of E. coli LpxC with Ki = 4.0 nM, Ki* = 0.5 nM, k5 = 1.9 min-1, and k6 = 0.18 min-1. CHIR-090 at low nanomolar levels inhibits LpxC orthologues from diverse Gram-negative pathogens, including P. aeruginosa, Neisseria meningitidis, and Helicobacter pylori. In contrast, CHIR-090 is a relatively weak competitive and conventional inhibitor (lacking slow, tight-binding kinetics) of LpxC from Rhizobium leguminosarum (Ki = 340 nM), a Gram-negative plant endosymbiont that is resistant to this compound. CHIR-090 is an excellent lead for the further development of new antibiotics targeting the lipid A pathway.

 

Chemical Formula: C24H27N3O5

 

Exact Mass: 437.1951

 

Molecular Weight: 437.496

 

Elemental Analysis: C, 65.89; H, 6.22; N, 9.60; O, 18.28

 

Synonym: 

 

CHIR-090

CHIR 090

CHIR090

 

Chemical Name:

N-[(2S,3R)-3-hydroxy-1-(hydroxyamino)-1-oxobutan-2-yl]-4-[2-[4-(morpholin-4-ylmethyl)phenyl]ethynyl]benzamide

 

InChi Key:

FQYBTYFKOHPWQT-VGSWGCGISA-N

 

InChi Code: 

InChI=1S/C24H27N3O5/c1-17(28)22(24(30)26-31)25-23(29)21-10-8-19(9-11-21)3-2-18-4-6-20(7-5-18)16-27-12-14-32-15-13-27/h4-11,17,22,28,31H,12-16H2,1H3,(H,25,29)(H,26,30)/t17-,22+/m1/s1

 

Smiles Code:

O=C(N[C@@H]([C@H](O)C)C(NO)=O)C1=CC=C(C#CC2=CC=C(CN3CCOCC3)C=C2)C=C1

 

 

Technical Data:

 

Appearance: White to off-white solid powder

Purity: >98% (or refer to the Certificate of Analysis)

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility: Soluble in DMSO, not in water

Shelf Life: >2 years if stored properly

Drug Formulation: This drug may be formulated in DMSO

Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code: 2934.99.9001

In Vitro:

CHIR-090 is a potent, slow, tight-binding inhibitor of the LpxC deacetylase from the hyperthermophile Aquifex aeolicus, and it has excellent antibiotic activity against P. aeruginosa and E. coli, as judged by disk diffusion assays. CHIR-090 is also a two-step slow, tight-binding inhibitor of Escherichia coli LpxC with Ki=4 nM. CHIR-090 at low nM levels inhibits LpxC orthologues from diverse Gram-negative pathogens, including Pseudomonas aeruginosa, Neisseria meningitidis, and Helicobacter pylori. In contrast, CHIR-090 is a relatively weak competitive and conventional inhibitor (lacking slow, tight-binding kinetics) of LpxC from Rhizobium leguminosarum (Ki=340 nM), a Gram-negative plant endosymbiont that is resistant to this compound. An E. coli construct in which the chromosomal lpxC gene is replaced by R. leguminosarum lpxC is resistant to CHIR-090 up to 100 μg/mL, or 400 times above the minimal inhibitory concentration for wild-type E. coli. CHIR-090, a very potent, slow, tight-binding inhibitor of Aquifex aeolicus LpxC, the sequence of which is 31 % identical to E. coli LpxC. CHIR-090 has remarkable antibiotic activity against E. coli and P. aeruginosa, comparable to ciprofloxacin, as judged by disk diffusion assays.

 

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.

 

 

References:

 

  1. Titecat M, Liang X, Lee CJ, Charlet A, Hocquet D, Lambert T, Pagès JM, Courcol R, Sebbane F, Toone EJ, Zhou P, Lemaitre N. High susceptibility of MDR and XDR Gram-negative pathogens to biphenyl-diacetylene-based difluoromethyl-allo-threonyl-hydroxamate LpxC inhibitors. J Antimicrob Chemother. 2016 Jun 20. pii: dkw210. [Epub ahead of print] PubMed PMID: 27330072.

 

  1. Kalinin D, Holl R. Insights into the zinc-dependent deacetylase LpxC: biochemical properties and inhibitor design. Curr Top Med Chem. 2016 Apr 13. [Epub ahead of print] PubMed PMID: 27072691.

 

  1. Vincent IM, Ehmann DE, Mills SD, Perros M, Barrett MP. Untargeted Metabolomics To Ascertain Antibiotic Modes of Action. Antimicrob Agents Chemother. 2016 Mar 25;60(4):2281-91. doi: 10.1128/AAC.02109-15. Print 2016 Apr. PubMed PMID: 26833150; PubMed Central PMCID: PMC4808186.

 

  1. Yao J, Bruhn DF, Frank MW, Lee RE, Rock CO. Activation of Exogenous Fatty Acids to Acyl-Acyl Carrier Protein Cannot Bypass FabI Inhibition in Neisseria. J Biol Chem. 2016 Jan 1;291(1):171-81. doi: 10.1074/jbc.M115.699462. Epub 2015 Nov 13. PubMed PMID: 26567338; PubMed Central PMCID: PMC4697154.

 

  1. Walkup GK, You Z, Ross PL, Allen EK, Daryaee F, Hale MR, O'Donnell J, Ehmann DE, Schuck VJ, Buurman ET, Choy AL, Hajec L, Murphy-Benenato K, Marone V, Patey SA, Grosser LA, Johnstone M, Walker SG, Tonge PJ, Fisher SL. Translating slow-binding inhibition kinetics into cellular and in vivo effects. Nat Chem Biol. 2015 Jun;11(6):416-23. doi: 10.1038/nchembio.1796. Epub 2015 Apr 20. PubMed PMID: 25894085; PubMed Central PMCID: PMC4536915.

 

Products are for research use only. Not for human use.

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