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Structure of 88887-87-0

Chemical Structure| 88887-87-0

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Product Citations

Product Citations

Li, Ruihao ; Xue, Yao-Peng ; Le, Steven T ; Tang, Wai Kwan ; Tolia, Niraj H ; Dantas, Gautam , et al.

Abstract: Next-generation antibiotics are threatened by an emerging resistance mechanism ─ enzymatic inactivation. The relevant enzymes ─ destructases (TDases) ─ are structural homologues of class A flavin monooxygenase (FMO) that oxidize antibiotics, leading to various inactive degradation products. Small molecule inhibitors of antibiotic-inactivating enzymes are critical clinical therapeutics used to manage bacterial resistance with combination therapy. While reversible TDase inhibitors have been reported, we sought to develop covalent inhibitors that are better aligned with clinically effective covalent inhibitors. Here, we report the design, chemical synthesis, and biochemical characterization of the first covalent irreversible inhibitors of TDases based on C9-derivatives of anhydrotetracycline (aTC). The reactive warheads were installed via a one-step Mannich reaction linking either an N-(1-methyl)cyclopropylamine or N-propargylamine group to the C9-position of the aTC D-ring via an amino methylene linkage. We also synthesized two nonspecific FMO inhibitors, N-(1-methyl)cyclopropylbenzylamine (1) and N-methyl-N-benzyl-propargylamine (2) as mechanistic probes to distinguish reactivity with the essential FAD cofactor in TDases via one- or two-electron transfer pathways, respectively. We evaluated the compounds as potential inhibitors of representative TDases from the two major classes─Type 1 (TetX6 and TetX7) and Type 2 (Tet50). The aTC-based compounds 3-5 inhibited both Type 1 and Type 2 TDases with notable differences in potency and inhibition mechanism. The inhibition of Type 1 TDases was more potent but reversible with no time dependence. The inhibition of Type 2 TDases was time-dependent and irreversible even after exhaustive dialysis, consistent with a covalent mechanism of inhibition. Molecular modeling of the inhibitors supports unique inhibitor binding modes for Type 1 and Type 2 TDases that are consistent with the observed differences in the inhibition modes. Blue light irradiation of the Type 2 TDase enhanced this reactivity. Treatment of Tet50 with probe molecules 1 and 2 under blue light exposure enabled the identification of covalent FAD adducts via mass spectrometry that are consistent with the expected one- and two-electron transfer reaction modes of the cyclopropylamine and propargylamine warheads with the FAD cofactor. At concentrations as low as 2 μg/mL, the aTC-based covalent inhibitors 3-5 recovered activity against E. coli overexpressing TDases. Our findings suggest that the inhibition of TDases through covalent trapping of the FAD cofactor is a viable strategy for overcoming TDase-mediated antibiotic resistance.

Keywords: antibiotic resistance ; destructase ; flavin monooxygenase ; covalent enzyme inhibition ; ; anyhydrotetracycline

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Alternative Products

Product Details of [ 88887-87-0 ]

CAS No. :88887-87-0
Formula : C4H10ClN
M.W : 107.58
SMILES Code : NC1(C)CC1.[H]Cl
MDL No. :MFCD11109576
InChI Key :GHILZUOTUJGCDH-UHFFFAOYSA-N
Pubchem ID :12953687

Safety of [ 88887-87-0 ]

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

Computational Chemistry of [ 88887-87-0 ] Show Less

Physicochemical Properties

Num. heavy atoms 6
Num. arom. heavy atoms 0
Fraction Csp3 1.0
Num. rotatable bonds 0
Num. H-bond acceptors 1.0
Num. H-bond donors 1.0
Molar Refractivity 28.94
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.

0.0
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

0.83
Log Po/w (WLOGP)?

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

1.24
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.

0.76
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

0.83
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

0.73

Water Solubility

Log S (ESOL):?

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

-1.03
Solubility 10.0 mg/ml ; 0.0933 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.

-0.96
Solubility 11.8 mg/ml ; 0.11 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

-0.58
Solubility 28.0 mg/ml ; 0.26 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.

-6.37 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

3.0
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 [ 88887-87-0 ]

* 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 [ 88887-87-0 ]

[ 88887-87-0 ] Synthesis Path-Downstream   1~1

  • 1
  • [ 97-08-5 ]
  • [ 88887-87-0 ]
  • 4-chloro-N-(1-methyl cyclopropyl)-3-nitro-benzenesulfonamide [ No CAS ]
 

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