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Chemical Structure| 53774-20-2 Chemical Structure| 53774-20-2

Structure of 53774-20-2

Chemical Structure| 53774-20-2

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Product Citations

Product Citations

Ohoueu, Marie-Josiane ;

Abstract: The synthesis of a series of compounds designed to act as inhibitors of metallo-βlactamase enzymes (MBLs), a sub-class of β-lactamases found in several clinically difficult to treat bacteria that are responsible for the widespread β-lactam antibiotic resistance, are described. The strategy involves the introduction of a functional group, such as an epoxide or thiirane, in the designed inhibitors capable of covalently binding the MBL targets and shutting them down irreversibly. This would prevent the enzymes from hydrolyzing the antibiotic drugs which would maintain their efficacy as a form of treatment. This was first attempted through the development of a convergent synthesis which involved the formation of L- and D-vinylglycine methyl ester, serving for the incorporation of the 3-membered ring, in a five-step synthetic pathway. This was subsequently introduced using coupling chemistry to a dipeptide. The intermediate dipeptide precursor synthesized through amino acid coupling was phenylglycine-serine (Phg-Ser) followed by a phenylacetic acid-serine (PAA-Ser), which both mimic an open lactam structure. They were subjected to halogenation to convert the serine alcohol functional group to a bromide for the alkylation reaction with the amino group contained in the protected vinylglycine. However, the bromination of Phg-Ser proved to be difficult while the formation of the desired tripeptide with the brominated PAA-Ser was not observed. Evidence of an alkene product was observed which was attributed to the acidic proton at the α-position favoring the elimination of the bromine. Those limitations led to the modification of the serine core to aspartic acid which was thought to circumvent the elimination issue by introducing the vinylglycine by amide bond formation rather than alkylation. Investigation with the phenylacetic-acid-aspartic acid dipeptide led to a promising route in which the coupling of the vinylglycine was achieved efficiently. The subsequent last steps of epoxidation of the alkene and deprotection seemed to be successful although optimization of these is still required. Another strategy for the development of covalent inhibitors was the synthesis of compounds inspired from L-captopril, an inhibitor of angiotensin converting enzyme (ACE) inhibitors which plays a role in heart attack. Here, the strategy involves the synthesis of an alkenecontaining intermediate with 2-methylprop-2-enoic acid or 2-methyl-3-butenoic acid through acylation of proline ethyl ester with the corresponding acyl chlorides. The intermediates were successfully obtained, enabling the formation of the epoxide and thiirane compounds. Subsequently, the ethyl ester hydrolysis was done to provide the final derivatives 1-(2-methyloxirane-2-carbonyl) pyrrolidine-2-carboxylic acid (82) and 1-(2-methylthiirane-2-carbonyl)pyrrolidine-2-carboxylic acid (83) with evidence of the formation of the desired 82 and 83. In the case of the longer chain analogues, 1-[2-(oxirane-2yl)propanoyl] pyrrolidine-2-carboylic acid (84) and 1-[2-(thiirane-2yl)propanoyl] pyrrolidine-2-carboylic acid (85), the deprotection led to the isolation of the final thiirane compound 85 in an overall 5% yield while this last deprotection step remains to be optimized to obtain 84. The synthetic pathway of the open lactam derivatives was overall successful with only the last two steps requiring further optimization which would provide a new class of β-lactamase inhibitors. The pathway for the development of the proline derivatives afforded efficiently one of the desired captopril derivatives while the purification of last step to isolate the remaining compounds needs to be improved. The strategy presented could be used in the future to provide further library compounds for MBL inhibition for further studies. General Introduction: This dissertation is composed of three separate chapters: (I) Introduction to β-lactamases and antimicrobial resistance, (II) Development of open lactam analogues as covalent inhibitors targeting metallo-β-lactamases, (III) Development of captopril-inspired compounds as covalent inhibitors of metallo-β-lactamases. The first chapter serves as introduction to the subject under the form of a mini review. The subsequent chapters investigate the strategies which have been explored in order to obtain the desired targets. They each are comprised of an introduction, results and discussion, and conclusion. Following the chapters is an appendix of relevant spectroscopic data related to the experimental procedures of the different chapters.

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Alternative Products

Product Details of [ 53774-20-2 ]

CAS No. :53774-20-2
Formula : C5H8O2
M.W : 100.12
SMILES Code : C=CC(C)C(O)=O
MDL No. :MFCD00042650
InChI Key :GQWNPIKWYPQUPI-UHFFFAOYSA-N
Pubchem ID :143088

Safety of [ 53774-20-2 ]

GHS Pictogram:
Signal Word:Danger
Hazard Statements:H227-H290-H314
Precautionary Statements:P210-P234-P260-P264-P280-P301+P330+P331+P310-P303+P361+P353+P310+P363-P304+P340+P310-P305+P351+P338+P310-P370+P378-P390-P403+P235-P405-P406-P501
Class:8
UN#:3265
Packing Group:

Computational Chemistry of [ 53774-20-2 ] Show Less

Physicochemical Properties

Num. heavy atoms 7
Num. arom. heavy atoms 0
Fraction Csp3 0.4
Num. rotatable bonds 2
Num. H-bond acceptors 2.0
Num. H-bond donors 1.0
Molar Refractivity 27.45
TPSA ?

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

37.3 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

1.22
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

1.11
Log Po/w (WLOGP)?

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

0.89
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.

0.79
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

0.34
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

0.87

Water Solubility

Log S (ESOL):?

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

-1.03
Solubility 9.39 mg/ml ; 0.0938 mol/l
Class?

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

Very soluble
Log S (Ali)?

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

-1.49
Solubility 3.27 mg/ml ; 0.0326 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

-0.06
Solubility 87.8 mg/ml ; 0.877 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

No
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.

-6.12 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.

0.56

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)

2.05
 

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Technical Information

Categories

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