Synthesis and pharmacological evaluation of pyrazine N-acylhydrazone derivatives designed as novel analgesic and anti-inflammatory drug candidates

• Published in: Bioorganic & medicinal chemistry 2010-07, Vol.18 (14), p.5007-5015
• Main Authors: Silva, Yolanda Karla Cupertino da, Augusto, Cristina Villarinho, Barbosa, Maria Letícia de Castro, Melo, Gabriela Muniz de Albuquerque, Queiroz, Aline Cavalcanti de, Dias, Thays de Lima Matos Freire, Júnior, Walfrido Bispo, Barreiro, Eliezer J., Lima, Lídia Moreira, Alexandre-Moreira, Magna Suzana
• Format: Article
• Language: English
• Subjects: Analgesics; Analgesics - chemical synthesis; Analgesics - chemistry; Analgesics - therapeutic use; Animals; Anti-inflammatory; Anti-Inflammatory Agents - chemical synthesis; Anti-Inflammatory Agents - chemistry; Anti-Inflammatory Agents - therapeutic use; Antinociceptive; Arthritis; Arthritis - chemically induced; Arthritis - drug therapy; Bioactive N-acylhydrazone; Biological and medical sciences; Bones, joints and connective tissue. Antiinflammatory agents; Ear - pathology; Edema - chemically induced; Edema - drug therapy; Female; Freund's Adjuvant; Hydrazones - chemical synthesis; Hydrazones - chemistry; Hydrazones - therapeutic use; Male; Medical sciences; Mice; Neuropharmacology; Pain - drug therapy; Peritonitis - chemically induced; Peritonitis - drug therapy; Pharmacology. Drug treatments; Pyrazines - chemical synthesis; Pyrazines - chemistry; Pyrazines - therapeutic use; Rats; Rats, Wistar; Zymosan
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2010.06.002

In this paper, we report the design, synthesis and pharmacological evaluation of a series of pyrazine N-acylhydrazone (NAH) derivatives (2a–s), planned by molecular simplification of prototype LASSBio-1018 (1). The series (2a–s) was evaluated in several animal models of pain and inflammation. All compounds presented important antinociceptive and anti-inflammatory profiles, especially compound 2o (LASSBio-1181), presenting a trimethoxylated phenyl moiety. This derivative 2o has shown better pharmacological profile than prototype 1, being also active in adjuvant-induced arthritis test in rats. In this paper, we report the synthesis and pharmacological evaluation of pyrazine N-acylhydrazone (NAH) derivatives (2a–s) designed as novel analgesic and anti-inflammatory drug candidates. This series was planned by molecular simplification of prototype 1 (LASSBio-1018), previously described as a non-selective cyclooxygenase inhibitor. Derivatives 2a–s were evaluated in several animal models of pain and inflammation, standing-out compound 2o (2-N′-[(E)-(3,4,5-trimethoxyphenyl) methylidene]-2-pyrazinecarbohydrazide; LASSBio-1181), that was also active in a murine model of chronic inflammation (i.e., adjuvant-induced arthritis test in rats) and can be considered a new analgesic and anti-inflammatory lead for drug development.