(E)-2-Cyano-3-(1H-Indol-3-yl)-N-Phenylacrylamide, a Hybrid Compound Derived from Indomethacin and Paracetamol: Design, Synthesis and Evaluation of the Anti-Inflammatory Potential

International Journal of Molecular Sciences

Renan Espírito-Santo¹  Cristiane Villarreal¹  Jamire Silva²  Maria de Almeida³  Ricardo Moura⁴  Vanda Santos⁴  Pablo Silva⁴  Sonaly Albino⁴  Maria Lima⁵ 

[1] Instituto Gonçalo Moniz, Fundação Oswaldo Cruz, Salvador 40296-710, BA, Brazil;Laboratório de Desenvolvimento e Síntese de Fármacos, Departamento de Farmácia, Universidade Estadual da Paraiba, Campina Grande 58429-500, PB, Brazil;Laboratório de Ensaios Farmacológicos, Departamento de Farmácia, Universidade Estadual da Paraíba, Campina Grande 58429-500, PB, Brazil;Programa de Pós-Graduação em Ciências Farmacêuticas, Universidade Estadual da Paraíba, Campina Grande 58429-500, PB, Brazil;Programa de Pós-Graduação em Ciências Farmacêuticas, Universidade Federal de Pernambuco, Recife 58429-500, PE, Brazil;

关键词: cytokines;    paw edema;    PGE₂;    phenylacrylamide;   

DOI  :  10.3390/ijms21072591

来源: DOAJ

【 摘 要 】

The compound (E)-2-cyano-3-(1H-indol-3-yl)-N-phenylacrylamide (ICMD-01) was designed and developed based on the structures of clinically relevant drugs indomethacin and paracetamol through the molecular hybridization strategy. This derivative was obtained by an amidation reaction between substituted anilines and ethyl 2-cyanoacetate followed by a Knoevenagel-type condensation reaction with indole aldehyde that resulted in both a viable synthesis and satisfactory yield. In order to assess the immunomodulatory and anti-inflammatory activity, in vitro assays were performed in J774 macrophages, and significant inhibitions (p < 0.05) of the production of nitrite and the production of cytokines (IL-1β and TNFα) in noncytotoxic concentrations were observed. The anti-inflammatory effect was also studied via CFA-induced paw edema in vivo tests and zymosan-induced peritonitis. In the paw edema assay, ICMD01 (50 mg kg⁻¹) showed satisfactory activity, as did the group treated with dexamethasone, reducing edema in 2–6 h. In addition, there was no significant inhibition of PGE₂, IL-1β or TNFα in vivo. Moreover, in the peritonitis assay that assesses leukocyte migration, ICMD-01 exhibited promising results. Therefore, these preliminary studies demonstrate this compound to be a strong candidate for an anti-inflammatory drug together with an improved gastrointestinal safety profile when compared to the conventional anti-inflammatory drugs.

【 授权许可】

Unknown