Bioorganic & Medicinal Chemistry ( IF 3.5 ) Pub Date : 2018-02-25 , DOI: 10.1016/j.bmc.2018.02.047 Cássio S. Meira , José Maurício dos Santos Filho , Caroline C. Sousa , Pâmela S. Anjos , Jéssica V. Cerqueira , Humberto A. Dias Neto , Rafael G. da Silveira , Helena M. Russo , Jean-Luc Wolfender , Emerson F. Queiroz , Diogo R.M. Moreira , Milena B.P. Soares
4-(Nitrophenyl)hydrazone derivatives of N-acylhydrazone were synthesized and screened for suppress lymphocyte proliferation and nitrite inhibition in macrophages. Compared to an unsubstituted N-acylhydrazone, active compounds were identified within initial series when hydroxyl, chloride and nitro substituents were employed. Structure-activity relationship was further developed by varying the position of these substituents as well as attaching structurally-related substituents. Changing substituent position revealed a more promising compound series of anti-inflammatory agents. In contrast, an N-methyl group appended to the 4-(nitrophenyl)hydrazone moiety reduced activity. Anti-inflammatory activity of compounds is achieved by modulating IL-1β secretion and prostaglandin E2 synthesis in macrophages and by inhibiting calcineurin phosphatase activity in lymphocytes. Compound SintMed65 was advanced into an acute model of peritonitis in mice, where it inhibited the neutrophil infiltration after being orally administered. In summary, we demonstrated in great details the structural requirements and the underlying mechanism for anti-inflammatory activity of a new family of hydrazone-N-acylhydrazone, which may represent a valuable medicinal chemistry direction for the anti-inflammatory drug development in general.
中文翻译:
N-N-酰基hydr的结构设计,合成和取代作用揭示了有效的免疫调节剂
合成了N-酰基hydr的4-(硝基苯基)hydr衍生物,并筛选了其在巨噬细胞中抑制淋巴细胞增殖和抑制亚硝酸盐的作用。与未取代的N-酰基hydr相比,当使用羟基,氯和硝基取代基时,在初始系列中鉴定出了活性化合物。通过改变这些取代基的位置以及连接与结构相关的取代基,进一步发展了结构-活性关系。取代基位置的变化揭示了更有希望的复合抗炎药系列。相反,N附加到4-(硝基苯基)hydr部分的-甲基基团降低了活性。通过调节巨噬细胞中IL-1β的分泌和前列腺素E2的合成以及抑制淋巴细胞中钙调磷酸酶磷酸酶的活性,可以实现化合物的抗炎活性。化合物SintMed65进入小鼠腹膜炎的急性模型,口服后抑制了中性粒细胞的浸润。总而言之,我们详细地证明了N-N-酰基new新家族的结构要求和抗炎活性的潜在机制,这可能代表了抗炎药物开发的重要医学化学方向。