Synthesis of N-pyridinyl(methyl)-1,2-dihydro-4-hydroxy-2-oxoquinoline-3-carboxamides and analogues and their anti-inflammatory activity in mice and rats.
The topical anti-inflammatory activity of a series of N-pyridinyl(methyl)1,2-dihydro-4-hydroxy-2-oxoquinoline-3-carboxamides, analogues of roquinimex, has been evaluated by measuring their inhibitory effect in the phorbol myristate acetate (PMA)-induced mouse ear swelling test, used as a screening test. All the eight carboxamides tested (9-16) exhibited significant inhibitory activity at 0.4 and 0.2 mM kg(-1). The most potent compound, the 6-bromo derivative 12, induced a 73% inhibition at 0.2 mM kg(-1). Pharmacomodulation was carried out by heterocycle opening and molecular simplification leading to pentafluorobenzoylacetamide 17, pentafluorocinnamamides 18 and 19, and pentafluorobenzaldimines 20 and 21. All the five compounds exerted a reduction in swelling (49-63% at 0.2 mM kg(-1)) comparable with ibuprofen (56%). Anti-inflammatory activity of the most efficient compounds was evaluated by carrageenan-induced rat paw oedema inhibition. The pentafluorobenzaldimine 20 showed the highest activity with an inhibition percentage of 85% at 0.2 mM kg(-1).
Collin
X
X
Laboratories de Chimie Organique et de Chimie Thérapeutique, Faculté de Pharmacie, Nantes, France.
Robert
J M
JM
Duflos
M
M
Wielgosz
G
G
Le Baut
G
G
Bobin-Dubigeon
C
C
Grimaud
N
N
Lang
F
F
Petit
J Y
JY
Robin-Dubigeon
C
C
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis*; D002351:Carrageenan; D004431:Ear, External / Q000473:pathology; D004487:Edema / Q000139:chemically induced / Q000517:prevention & control; D005528:Foot / Q000473:pathology; D008297:Male; D051379:Mice; D011725:Pyridines / Q000138:chemical synthesis* / Q000494:pharmacology*; D015363:Quinolones / Q000138:chemical synthesis* / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013755:Tetradecanoylphorbol Acetate
D000894:Anti-Inflammatory Agents, Non-Steroidal; D011725:Pyridines; D015363:Quinolones; D002351:Carrageenan; D013755:Tetradecanoylphorbol Acetate