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Rodriguez, Diego F. ; Duran-Osorio, Francisca ; Duarte, Yorley , et al. Pharmaceutics,2022,14(1),33. DOI: 10.3390/pharmaceutics14010033 PubMed ID: 35056929
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Abstract: Green chemistry implementation has led to promising results in waste reduction in the pharmaceutical industry. However, the early sustainable development of pharmaceutically active compounds and ingredients remains a considerable challenge. Herein, we wish to report a green synthesis of new pharmaceutically active peptide triazoles as potent factor Xa inhibitors, an important drug target associated with the treatment of diverse cardiovascular diseases. The new inhibitors were synthesized in three steps, featuring cycloaddition reactions (high atom economy), microwave-assisted organic synthesis (energy efficiency), and copper nanoparticle catalysis, thus featuring Earth-abundant metals. The molecules obtained showed FXa inhibition, with IC50-values as low as 17.2 μM and no associated cytotoxicity in HEK293 and HeLa cells. These results showcase the environmental potential and chemical implications of the applied methodologies for the development of new molecules with pharmacological potential.
Keywords: DOACs ; FXa inhibitors ; Ullmann-Goldberg reaction ; click chemistry ; drug discovery ; green chemistry ; microwave synthesis
Purchased from AmBeed: 20196-21-8 ; 109-11-5 ; 675-20-7 ; 766-97-2
CAS No. : | 109-11-5 | MDL No. : | MFCD00631009 |
Formula : | C4H7NO2 | Boiling Point : | No data available |
Linear Structure Formula : | - | InChI Key : | VSEAAEQOQBMPQF-UHFFFAOYSA-N |
M.W : | 101.10 | Pubchem ID : | 66953 |
Synonyms : |
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Signal Word: | Warning | Class: | |
Precautionary Statements: | P264-P280-P302+P352-P337+P313-P305+P351+P338-P362+P364-P332+P313 | UN#: | |
Hazard Statements: | H315-H319 | Packing Group: | |
GHS Pictogram: |
* 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 |
---|---|---|
With 8-quinolinol; potassium carbonate;copper(l) iodide; In dimethyl sulfoxide; at 130℃; | A mixture of 5-chloro-N-((1-(4-iodophenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide 1-6 prepared in Example 1 (33 mg, 0.074 mmol), <strong>[109-11-5]3-morpholinone</strong> prepared above (22 mg, 0.218 mmol), 8-hydroxyquinoline (7 mg, 0.048 mmol) and K2CO3 (30 mg, 0.217 mmol) in DMSO (0.5 mL) was degassed before being charged with CuI (14 mg, 0.073 mmol). The mixture in a sealed tube was heated at 130 C. overnight. The mixture was then purified by HPLC to give the title compound (3 mg). MS 417.0 and 419.0 (M+H, Cl pattern). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
11% | To a suspension of morpholin-3-one (29 mg, 0.288 mmol) in THF (2 mL) was added NaH (16.14 mg, 0.336 mmol). After stirring the mixture for 5 mi (3- (bromomethyl)phenyl)boronic acid (41.3 mg, 0.192 mmol) was added and the resulting mixture was stirred at room temperature for 2 h. Water (1 mL) was added, followed byphosphoric acid, potassium salt (61.2 mg, 0.288 mmol) and 7-bromo-5-(1-(tetrahydro-2H-pyran-4-yl)- 1 H- 1,2,3 -triazol-5-yl)pyrrolo[2, 1 -f] [1 ,2,4]triazin-4-amine (35 mg, 0.096 mmol). The reaction vessel was evacuated, backfilled with N2 and then degassed by bubbling N2 while being sonicated. Tetrakis triphenylphosphine (11.11 mg, 9.61 .imol) was added and the degassing process was repeated. The reaction mixture was heated at140 C in a microwave for 1 h. The reaction mixture was cooled, filtered, washed with water and extracted with ethyl acetate (10 mL x 3). The organic layers were combined, dried and concentrated. The residue purified by preparative LCMS method C to obtain 4-(3 -(4-amino-5-( 1 -(tetrahydro-2H-pyran-4-yl)- 1 H- 1,2,3 -triazol-5 -yl)pyrrolo[2, 1 -f] [1,2,4] triazin-7-yl)benzyl)morpholin-3-one (5.3 mg, 11% yield). LC/MS (M+H) =475.15. ?H NMR (500 MHz, DMSO-d6) oe 2.0 (m, 2H), 2.16 (m, 2H), 3.32 (t, 2H), 3.37 (m, 2H), 3.85 (t, 2H), 3.93 (m, 3H), 4.14(s, 2H), 4.64 (s, 2H), 7.27 (m, 2H), 7.50 (t, 1H), 7.87 (s, 1H), 7.96 (m, 2H), 8.10 (m, 1H). |
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