Synthesis, characterization and pharmacological evaluation of 1-(2-chloro-6-fluorophenyl)-5-methylindolin-2-one: a new anti-inflammatory compound with reduced gastric ulceration properties.
The new compound 1-(2-chloro-6-fluorophenyl)-5-methylindolin-2-one (1), designed using the prodrug approach, was easily obtained in 85% yield and characterized by nuclear magnetic resonance, elemental analysis, mass spectrometry and infrared spectroscopy. The lactam 1 showed anti-inflammatory and analgesic activity comparable to that of the COX-2 inhibitor lumiracoxib, without gastro-ulceration effects. Stability studies demonstrated that the lactam function was stable and did not hydrolyze in pH 1.2 or 7.4. Furthermore, using a thioglycollate-induced peritonitis model, compound 1 was shown to inhibit cell migration by 50.4%, while lumiracoxib inhibited it by 18%. This compound represents a new non-ulcerogenic prototype for the treatment of chronic inflammatory diseases.
Lapdesf-Laboratório de Pesquisa e Desenvolvimento de Fármacos, Departamento de Fármacos e Medicamentos, Faculdade de Ciências Farmacêuticas-UNESP Rodovia Araraquara Jaú Km. 01, 14801-902, Araraquara, SP, Brazil. santosjl@fcfar.unesp.br
Jean Leandro
JL
dos Santos
Rafael
R
Chelucci
Richard
R
Chiquetto
Man Chin
MC
Chung
Michel Leandro
ML
Campos
Rosangela Gonçalves
RG
Peccinini
D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000009:adverse effects / Q000138:chemical synthesis* / Q000494:pharmacology*; D002465:Cell Movement / Q000187:drug effects; D052246:Cyclooxygenase 2 Inhibitors / Q000009:adverse effects / Q000138:chemical synthesis; D004008:Diclofenac / Q000009:adverse effects / Q000031:analogs & derivatives / Q000494:pharmacology; D004355:Drug Stability; D005260:Female; D005753:Gastric Mucosa / Q000187:drug effects*; D006863:Hydrogen-Ion Concentration; D007211:Indoles / Q000494:pharmacology*; D007213:Indomethacin / Q000009:adverse effects / Q000494:pharmacology; D007769:Lactams / Q000009:adverse effects / Q000138:chemical synthesis* / Q000494:pharmacology*; D008297:Male; D051379:Mice; D011355:Prodrugs / Q000009:adverse effects / Q000138:chemical synthesis / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013276:Stomach Ulcer / Q000139:chemically induced
C555769:1-(2-chloro-6-fluorophenyl)-5-methylindolin-2-one; D000700:Analgesics; D000893:Anti-Inflammatory Agents; D052246:Cyclooxygenase 2 Inhibitors; D007211:Indoles; D007769:Lactams; D011355:Prodrugs; D004008:Diclofenac; C473384:lumiracoxib; D007213:Indomethacin