Chemistry around imidazopyrazine and ibuprofen: discovery of novel fatty acid amide hydrolase (FAAH) inhibitors.
Based on the imidazo-[1,2-a]-pyrazin-3-(7H)-one scaffold, a dual action prodrug has been designed for combining antioxidant and anti-inflammatory activities, possibly unmasked upon oxidation. The construction of the target-molecule requires two building blocks, namely a 2-amino-1,4-pyrazine and a 2-ketoaldehyde. Attempts to synthesize the 2-ketoaldehyde (5a) derived from ibuprofen failed, but led to the corresponding 2-ketoaldoxime (7a) which could not be condensed with the pyrazine synthons. However, a model compound, i.e. phenylglyoxal aldoxime, reacted well under microwave activation to furnish novel imidazo[1,2-a]-pyrazine-3-(7H)-imine derivatives (18a,b). These heterobicycles behave as antioxidants by inhibiting the lipid peroxidation, and one compound (18b) is endowed with a significant anti-inflammatory effect in a cellular test. Unexpectedly, all the synthetic intermediates derived from ibuprofen are good inhibitors of FAAH, the most active compound (4a) featuring the 1,3-dithian-2-yl motif.
De Wael
Frédéric
F
Institute of Condensed Matter and Nanoscience, Unité de chimie organique et médicinale, Université catholique de Louvain, Place Louis Pasteur 1, B-1348 Louvain-la-Neuve, Belgium.
Muccioli
Giulio G
GG
Lambert
Didier M
DM
Sergent
Thérèse
T
Schneider
Yves-Jacques
YJ
Rees
Jean-François
JF
Marchand-Brynaert
Jacqueline
J
D000447:Aldehydes / Q000737:chemistry; D000581:Amidohydrolases / Q000037:antagonists & inhibitors*; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000975:Antioxidants / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D018938:Caco-2 Cells; D063385:Cannabinoid Receptor Modulators / Q000378:metabolism; D055808:Drug Discovery / Q000379:methods*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D007052:Ibuprofen / Q000737:chemistry*; D010091:Oximes / Q000737:chemistry; D011719:Pyrazines / Q000737:chemistry; D011720:Pyrazoles / Q000737:chemistry*; D000099252:Fatty Acid Amide Hydrolases
D000447:Aldehydes; D000581:Amidohydrolases; D000893:Anti-Inflammatory Agents; D000975:Antioxidants; D063385:Cannabinoid Receptor Modulators; D004791:Enzyme Inhibitors; D007052:Ibuprofen; D010091:Oximes; D011719:Pyrazines; D011720:Pyrazoles; D000099252:Fatty Acid Amide Hydrolases; C026262:imidazopyrazole; C079424:2-aminopyrazine