Synthesis, docking studies and anti-inflammatory activity of 4,5,6,7-tetrahydro-2H-indazole derivatives.
A regioselective synthesis of 2,3-disubstituted tetrahydro-2H-indazols, mediated by alpha-zirconium sulfophenylphosphonate-methanephosphonate, was reported. Docking studies into the catalytic site of COX-2 were used to identify potential anti-inflammatory lead compounds. Two lead derivatives were chosen endowed with good binding energies and good ADME profiling. The biological in vivo evaluation of these compounds in two different experimental models (Freund's adjuvant-induced arthritis and carrageenan-induced oedema) proved the presence of anti-inflammatory activity. Noteworthy, both compounds evidenced the lack of any gastric injury even at high doses in gastric ulcerogenic assays.
Rosati
Ornelio
O
Dipartimento di Chimica e Tecnologia del Farmaco, Via del liceo 1, University of Perugia, 06123 Perugia (PG), Italy. ornros@unipg.it
Curini
Massimo
M
Marcotullio
Maria Carla
MC
Macchiarulo
Antonio
A
Perfumi
Marina
M
Mattioli
Laura
L
Rismondo
Francesco
F
Cravotto
Giancarlo
G
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D001169:Arthritis, Experimental / Q000188:drug therapy / Q000473:pathology; D002351:Carrageenan; D052246:Cyclooxygenase 2 Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D005528:Foot / Q000473:pathology; D005620:Freund's Adjuvant; D007191:Indazoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D010147:Pain Measurement / Q000187:drug effects; D051381:Rats; D013276:Stomach Ulcer / Q000139:chemically induced; D013329:Structure-Activity Relationship
D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D007191:Indazoles; D007202:Indicators and Reagents; D002351:Carrageenan; D005620:Freund's Adjuvant