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Nicholas O. Schneider ; Kendra Gilreath ; Daniel J. Burkett , et al. Pharmaceuticals,2024,17(5):570. DOI: 10.3390/ph17050570
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Abstract: Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase which plays a center role in the phosphorylation of a wide variety of proteins, generally leading to their inactivation. As such, GSK-3 is viewed as a therapeutic target. An ever-increasing number of small organic molecule inhibitors of GSK-3 have been reported. Phenylmethylene hydantoins are known to exhibit a wide range of inhibitory activities including for GSK-3β. A family of fourteen 2-heterocycle substituted methylene hydantoins (14, 17–29) were prepared and evaluated for the inhibition of GSK-3β at 25 μM. The IC50 values of five of these compounds was determined; the two best inhibitors are 5-[(4′-chloro-2-pyridinyl)methylene]hydantoin (IC50 = 2.14 ± 0.18 μM) and 5-[(6′-bromo-2-pyridinyl)methylene]hydantoin (IC50 = 3.39 ± 0.16 μM). The computational docking of the compounds with GSK-3β (pdb 1q41) revealed poses with hydrogen bonding to the backbone at Val135. The 5-[(heteroaryl)methylene]hydantoins did not strongly inhibit other metalloenzymes, demonstrating poor inhibitory activity against matrix metalloproteinase-12 at 25 μM and against human carbonic anhydrase at 200 μM, and were not inhibitors for Staphylococcus aureus pyruvate carboxylase at concentrations >1000 μM.
Keywords: nitrogen heterocycles ; glycogen synthase kinase 3β ; computational docking
Purchased from AmBeed: 63071-13-6 ; 53547-60-7 ; 31181-90-5 ; 34160-40-2 ; 4985-92-6 ; 1121-60-4 ; 54221-96-4 ; 55589-47-4 ; 500-22-1 ; 1805434-14-3
CAS No. : | 34160-40-2 | MDL No. : | MFCD02683546 |
Formula : | C6H4BrNO | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | QWFHFNGMCPMOCD-UHFFFAOYSA-N |
M.W : | 186.01 | Pubchem ID : | 2757009 |
Synonyms : |
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Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | Packing Group: | N/A |
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 |
---|---|---|
To a solution of <strong>[103291-07-2]5-bromo-2-fluoroanisole</strong> (200 mg, 0.98 mmol, 1 equiv) in anhydrous THF was added granules of magnesium (24 mg, 0.98 mmol, 1 equiv) under nitrogen. The mixture was heated to 60 C for 2 h. After reaching room temperature, 6-bromopyridin-2-yl carboxaldehyde (182 mg, 0.98 mmol, 1 equiv) was added and the reaction mixture was heated to 80 C and stirred overnight at 80 C. The reaction was cooled to room temperature, quenched with brine and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated to dryness under vacuum. The product was used in the next step without further purification. C13H11BrFNO2; MW 312. |
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