Ligand-based design, synthesis and primary in vivo screening of pyrrole derivatives as potential tricyclic anti-inflammatory agents.
Twelve new compounds were designed as 5-aryl-1H-pyrrole analogs of celecoxib (CAS 169590-42-5) and were synthesized by Paal-Knorr cyclization in three series according to 1H-substitution: derivatives with salicylic acid, pyrazolone or isonicotinamide residues. The average physico-chemical and steric similarity between the prototype and the new analogs (completed with two previously synthesized related products) was assessed to be 82 % and therefore considered as a reliable prerequisite for spatial compatibility and effective binding to the cyclooxygenase (COX) enzymes. The anti-inflammatory effects were determined in acute inflammation model using the carrageenan-induced rat paw edema assay on male Wistar rats (180-200 g) at doses of 10, 20 and 40 mg/kg, i.p. Six of the new products showed higher percent of inhibition (up to 100 %) compared to the highly selective COX-2 inhibitor celecoxib and the nonselective indometacin (CAS 53-86-1) used as reference compounds. Ethyl 1-(1,5-di-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-4-pyrazolyl)-2-methyl-5-phenyl-1H-3-pyrrolecarboxylate (2b), ethyl 5-(4-chlor-ophenyl)-2-methyl-1-[(4-pyridylcarbonyl) amino]-1H-3-pyrrolecarboxylate (3c) and 5-[3-acetyl-2-methyl-5-(4-methylphenyl)-1H-1-pyrrolyl] -2-hydroxybenzoic acid (4b) were pointed out as the most active representatives of each of the three tested sub-series.
Bijev
Atanas
A
Department Organic Synthesis and Fuels, University of Chemical Technology and Metallurgy, Sofia, Bulgaria. a.bijev@uctm.edu
Yaneva
Diana
D
Bocheva
Adriana
A
Stoev
Georgi
G
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000633:toxicity; D001522:Behavior, Animal / Q000187:drug effects; D002351:Carrageenan; D000068579:Celecoxib; D002855:Chromatography, Thin Layer; D052246:Cyclooxygenase 2 Inhibitors / Q000138:chemical synthesis*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology; D005528:Foot / Q000473:pathology; D007274:Injections, Intraperitoneal; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D011720:Pyrazoles / Q000138:chemical synthesis*; D011758:Pyrroles / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000633:toxicity; D051381:Rats; D017208:Rats, Wistar; D021241:Spectrometry, Mass, Electrospray Ionization; D013055:Spectrophotometry, Infrared; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D008024:Ligands; D011720:Pyrazoles; D011758:Pyrroles; D013449:Sulfonamides; D002351:Carrageenan; D000068579:Celecoxib