Mota Fernanda Virginia Barreto, de Araújo Neta Marlene Saraiva, de Souza Franco Eryvelton, Bastos Isla Vanessa Gomes Alves, da Araújo Larissa Cardoso Correia, da Silva Sandra Cabral, de Oliveira Tatiane Bezerra, Souza Eduarda Karynne, de Almeida Valderes Moraes, Ximenes Rafael Matos, de Sousa Maia Maria Bernadete, Junior Francisco Jaime Bezerra Mendonça, Marchand Pascal, de Faria Antônio Rodolfo, da Silva Teresinha Gonçalves
Departamento de Antibióticos , Universidade Federal de Pernambuco (UFPE) , Rua Prof. Arthur Sá, s/n , CEP 50560-901 , Recife-PE , Brazil . Email:
Departamento de Ciências Farmacêuticas , Universidade Federal de Pernambuco-UFPE , Rua Prof. Arthur de Sá, s/n , CEP 50470-521 , Recife-PE , Brazil.
Medchemcomm. 2019 Sep 12;10(11):1916-1925. doi: 10.1039/c9md00276f. eCollection 2019 Nov 1.
The aim of this study was to investigate the anti-inflammatory effects of two new isoxazoline-acylhydrazone derivatives: '-(4-methoxybenzylidene)-6-(4-nitro-benzoyl)-3,5,6,6-tetrahydro-4-pyrrolo[3,2-]isoxazole-3-carbohydrazide (R-123) and '-(4-chlorobenzylidene)-6-(4-chlorobenzoyl)-3,5,6,6-tetrahydro-4-pyrrolo[3,2-]isoxazole-3-carbohydrazide (R-99). An air pouch induced by carrageenan was used for screening the best dose of R-99 and R-123. Using this mouse model, leukocyte migration and cytokine levels (TNF-α and IL-1β) were determined. Paw edema induced by several phlogistic agents and vascular permeability induced by acetic acid were employed to investigate the mechanism of action of the isoxazoline-acylhydrazone derivatives. A docking study was performed with the human histamine H1 receptor to investigate potential antihistaminic activity. Treatment with the compounds reduced leukocyte migration in the air pouch at all doses tested. TNF-α and IL-1β levels were similarly reduced by the two compounds. Vasoactive amines were inhibited in models of paw edema induced by several agents and vascular permeability induced by acetic acid. The docking study suggests that R-99 and R-123 may be inhibitors of the histamine H1 receptor. In conclusion, the results indicate that R-99 and R-123 exhibit promising anti-inflammatory activity related to their ability to inhibit TNF-α, IL-1β, and vasoactive amine production, as well as reduce leukocyte migration and inhibit mast cell degranulation.
α-(4-甲氧基亚苄基)-6-(4-硝基苯甲酰基)-3,5,6,6-四氢-4-吡咯并[3,2-b]异恶唑-3-碳酰肼（R-123）和α-(4-氯亚苄基)-6-(4-氯苯甲酰基)-3,5,6,6-四氢-4-吡咯并[3,2-b]异恶唑-3-碳酰肼（R-99）。采用角叉菜胶诱导的气袋模型筛选R-99和R-123的最佳剂量。利用该小鼠模型，测定白细胞迁移和细胞因子水平（TNF-α和IL-1β）。采用多种炎性介质诱导的爪肿胀以及乙酸诱导的血管通透性来研究异恶唑啉酰腙衍生物的作用机制。对人组胺H1受体进行对接研究，以探究潜在的抗组胺活性。在所测试的所有剂量下，用这些化合物处理均可减少气袋中的白细胞迁移。这两种化合物同样降低了TNF-α和IL-1β水平。在多种介质诱导的爪肿胀模型以及乙酸诱导的血管通透性模型中，血管活性胺受到抑制。对接研究表明，R-99和R-123可能是组胺H1受体的抑制剂。总之，结果表明，R-99和R-123具有良好的抗炎活性，这与其抑制TNF-α、IL-1β和血管活性胺生成的能力有关，同时还能减少白细胞迁移并抑制肥大细胞脱颗粒。
