Pharmacological evaluation and preparation of nonsteroidal anti-inflammatory drugs containing an N-acyl hydrazone subunit.
A series of anti-inflammatory derivatives containing an N-acyl hydrazone subunit (4a-e) were synthesized and characterized. Docking studies were performed that suggest that compounds 4a-e bind to cyclooxygenase (COX)-1 and COX-2 isoforms, but with higher affinity for COX-2. The compounds display similar anti-inflammatory activities in vivo, although compound 4c is the most effective compound for inhibiting rat paw edema, with a reduction in the extent of inflammation of 35.9% and 52.8% at 2 and 4 h, respectively. The anti-inflammatory activity of N-acyl hydrazone derivatives was inferior to their respective parent drugs, except for compound 4c after 5 h. Ulcerogenic studies revealed that compounds 4a-e are less gastrotoxic than the respective parent drug. Compounds 4b-e demonstrated mucosal damage comparable to celecoxib. The in vivo analgesic activities of the compounds are higher than the respective parent drug for compounds 4a-b and 4d-e. Compound 4a was more active than dipyrone in reducing acetic-acid-induced abdominal constrictions. Our results indicate that compounds 4a-e are anti-inflammatory and analgesic compounds with reduced gastrotoxicity compared to their respective parent non-steroidal anti-inflammatory drugs.
School of Pharmaceutical Science, State University of São Paulo (UNESP), Rodovia Araraquara Jaú Km. 01, Araraquara, São Paulo 14801-902, Brazil. trfmelo@gmail.com.
Thais Regina Ferreira
TR
de Melo
School of Pharmaceutical Science, State University of São Paulo (UNESP), Rodovia Araraquara Jaú Km. 01, Araraquara, São Paulo 14801-902, Brazil. rafaelchelucci@hotmail.com.
Rafael Consolin
RC
Chelucci
School of Pharmaceutical Science, State University of São Paulo (UNESP), Rodovia Araraquara Jaú Km. 01, Araraquara, São Paulo 14801-902, Brazil. mariaelisalopes@yahoo.com.br.
Maria Elisa Lopes
ME
Pires
School of Pharmaceutical Science, State University of São Paulo (UNESP), Rodovia Araraquara Jaú Km. 01, Araraquara, São Paulo 14801-902, Brazil. luizdutra_qf@yahoo.com.br.
Luiz Antonio
LA
Dutra
School of Pharmaceutical Science, State University of São Paulo (UNESP), Rodovia Araraquara Jaú Km. 01, Araraquara, São Paulo 14801-902, Brazil. kakabarbieri85@yahoo.com.br.
Karina Pereira
KP
Barbieri
School of Pharmaceutical Science, State University of São Paulo (UNESP), Rodovia Araraquara Jaú Km. 01, Araraquara, São Paulo 14801-902, Brazil. bosquesi@fcfar.unesp.br.
Priscila Longhin
PL
Bosquesi
Faculty of Pharmaceutical Science, University of São Paulo, Av. Professor Lineu Prestes 580, São Paulo 05508-900, SP, Brazil. gustavo.trossini@gmail.com.
Gustavo Henrique Goulart
GH
Trossini
School of Pharmaceutical Science, State University of São Paulo (UNESP), Rodovia Araraquara Jaú Km. 01, Araraquara, São Paulo 14801-902, Brazil. chungmc@fcfar.unesp.br.
Man Chin
MC
Chung
School of Pharmaceutical Science, State University of São Paulo (UNESP), Rodovia Araraquara Jaú Km. 01, Araraquara, São Paulo 14801-902, Brazil. santosjl@fcfar.unesp.br.
Jean Leandro
JL
dos Santos
D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D000068579:Celecoxib; D051545:Cyclooxygenase 1 / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D015195:Drug Design; D006471:Gastrointestinal Hemorrhage / Q000139:chemically induced; D006835:Hydrazones / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D007249:Inflammation / Q000188:drug therapy; D008297:Male; D051379:Mice; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D011485:Protein Binding; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013449:Sulfonamides / Q000494:pharmacology
D000700:Analgesics; D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D006835:Hydrazones; D011720:Pyrazoles; D013449:Sulfonamides; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C489691:Ptgs2 protein, rat; D000068579:Celecoxib