Structure of 2-Bromoethylamine HBr
CAS No.: 2576-47-8
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The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
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Novel cationic dihydropyrrol-2-one compounds as antimicrobial agents and quorum sensing inhibitors
Suresh, Dittu ; Yu, Tsz Tin ; Kuppusamy, Rajesh ; Sabir, Shekh ; Das, Theerthankar ; Black, David StC , et al.
Abstract: Antimicrobial resistance has grown to become a global crisis consistently participating in the death of millions worldwide and accumulating costs on healthcare. Quorum sensing inhibition is a new alternative antimicrobial strategy that has been gaining attention due to its ability to suppress the resistance of Pseudomonas aeruginosa (PA). This approach shows great potential in overcoming bacterial resistance and could provide a much needed substitute to conventional antibiotics in the future. PA has 3 main quorum sensing systems of which the Las system has been identified to be the most viable therapeutic target. In this study, we report the synthesis of a library of novel broad-spectrum quorum sensing inhibitors from the dihydroyrrol-2-one scaffold to form urea and imidazolium analogues. Molecular docking was performed in parallel to synthesis to aid design. It also confirmed that the molecules comfortably occupy the ligand binding domain in addition to potential key interactions commonly present in LasR inhibitors. As predicted, these compounds displayed low bactericidal effects against P. aeruginosa with most compounds exhibiting MIC of > 250 μM, while maintaining moderate activity towards Escherichia coli with the most potent compound having an MIC of 32 μM. The greatest bactericidal effects were present on Staphylococcus aureus with the thiourea based molecule 10c showed the highest antibacterial activity with MIC of 16 µM. Furthermore, several molecules displayed highly potent quorum sensing inhibitory activity with compounds 10g and 9e both demonstrating over 70% inhibition respectively of the LasR system at 16 µM. These compounds also expressed inhibition of pyocyanin within P. aeruginosa and haemolytic assay indicates a low level of cell lysis and hence low toxicity of the compounds, further demonstrating the potential of these novel compounds.
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Keywords: Antibacterials ; Bacterial resistance ; Quorum sensing ; Pseudomonas Aeruginosa ; Broad–spectrum ; Dihydropyrrol-2-one
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CAS No. : | 2576-47-8 |
Formula : | C2H7Br2N |
M.W : | 204.89 |
SMILES Code : | NCCBr.[H]Br |
MDL No. : | MFCD00012886 |
InChI Key : | WJAXXWSZNSFVNG-UHFFFAOYSA-N |
Pubchem ID : | 2774217 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 5 |
Num. arom. heavy atoms | 0 |
Fraction Csp3 | 1.0 |
Num. rotatable bonds | 1 |
Num. H-bond acceptors | 1.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 31.23 |
TPSA ? Topological Polar Surface Area: Calculated from |
26.02 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
0.0 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.02 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
-2.54 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
1.16 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
0.28 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
-0.02 |
Log S (ESOL):? ESOL: Topological method implemented from |
-1.69 |
Solubility | 4.21 mg/ml ; 0.0206 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-1.16 |
Solubility | 14.3 mg/ml ; 0.0698 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-1.14 |
Solubility | 14.9 mg/ml ; 0.0728 mol/l |
Class? Solubility class: Log S scale |
Soluble |
GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg |
Low |
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg |
No |
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) |
No |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
No |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
No |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
No |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
No |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-6.83 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
Ghose? Ghose filter: implemented from |
None |
Veber? Veber (GSK) filter: implemented from |
0.0 |
Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
Muegge? Muegge (Bayer) filter: implemented from |
2.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.55 |
PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
Brenk? Structural Alert: implemented from |
1.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<1.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
2.07 |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86.1% | With triethylamine; In tetrahydrofuran; | EXAMPLE 11 Naphthalenesulfonamide, 5-(dimethylamino)-N-(2-bromoethyl) A suspension of 5-dimethylaminonaphthalene-1-sulfonyl chloride (50.0 g, 0.185 mol) and 2-bromoethylamine hydro-bromide (40.4 g, 0.197 mol) in THF (500 mL) was cooled to 2 C. A solution of triethylamine (38.5 g, 0.380 mol) in THF (250 mL) was added dropwise over a 2 h period while maintaining the internal temperature below 6 C. After complete addition the mixture was stirred at ambient temperature for 17 h. The mixture was clarified then concentrated to an orange oil which was chromatographed over silica (2.2 kg) packed and eluted with hexanes-EtOAc (3:1). Fractions (500 mL) containing the purified product were combined, clarified, then concentrated to a damp solid. This material was triturated in hexanes (250 mL), collected on a filter, washed with hexanes (50 mL) then dried to constant weight in vacuo at 40 C. to give 56.9 g (86.1% yield) of product as a off-white crystalline solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In dichloromethane; at 0 - 20℃;Inert atmosphere; | General procedure: To a solution of 2-bromoethylamine hydrobromide (for 12a-j) (1 equiv.) and 2.5 equiv. of triethylamine in dry DCM (5mL), 0.83 equiv. of commercially available arylsulfonyl chloride (11a-j) were added at 0C under nitrogen atmosphere. Then, the reaction mixture was stirred at room temperature until the complete conversion of the arylsulfonyl chloride as controlled by TLC. DCM was then added and the organic layer was washed with water and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to provide the desired product used for the synth esis of compound 7 without further purification. Compound 13 was obtained using 1 equiv. of 3-bromopropylamine hydrobromide and 0.83 equiv. of 4-methoxybenzenesulfonyl chloride following the same general procedure used for compounds 12a-j. |
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