新型肽脱甲酰基酶(PDF)抑制剂的研究(Ⅰ)——含异(口恶)唑的丁二酰异羟肟酸衍生物的设计与合成  

A novel bacterial peptide deformylase inhibitor:synthesis of succinate hydroxamate analogues containing isoxazole substitute

作　　者：汤立达[1] 贾炯[1] 徐为人[2] 张大同[1] 张士俊[2] 郑晓平[1] 王平保[2] 冯勇[1] 郑洪艳[2] 李炎[1] 刘登科[2] 孟丽娟[1] 任戎[2] 王建武[1] 

机构地区：[1]山东大学化学与化工学院,济南250100 [2]天津药物研究院,天津300193

出　　处：《中国新药杂志》2006年第10期797-801,共5页Chinese Journal of New Drugs

基　　金：国家重大基础研究前期研究专项(2003CCA027)

摘　　要：目的:发现新的肽脱甲酰基酶(PDF)抑制剂先导化合物。方法:在异(?)唑环杂原子作为电子对供体替代羰基氧原子与受体形成氢键的新思路指导下,设计并合成了一系列新型含异(口恶)唑的β-戊基-丁二酰异羟肟酸衍生物,其结构经核磁共振(NMR)、质谱(MS)等证明,并对部分该类化合物进行了体外抑菌实验。结果:体外抑菌实验表明,该类化合物具有一定的抗菌活性。结论:以异(口恶)唑环杂原子作为电子对供体替代肽分子中的羰基氧原子与受体形成氢键的设想是成立的,为进一步优化本类化合物结构,乃至对类肽新药的设计具有重要意义。Objective： To develop lead compounds classified as a nonpeptide bacterial peptide deformylase （PDF） inhibitor. Methods： Based on a rational that a heteroatom in isoxazole ring may be used as electron donor to form a hydrogen bond with receptors instead of oxygen atom in a carboxyl group of PDF, a series of 2-n-pentyl succinate hydroxamate derivatives containing isoxazole substitutes were newly synthesized. The structures of such new derivatives were confirmed by NMR and MS. An anti-bacterial assay in vitro for the new derivatives was conducted. Results： The new derivatives showed antibacterial activities. Conclusion： Isoxazole ring could be used as the substitute of amide to offer electron pairs for the formation of hydrogen bond with receptors.

关 键 词：异唑 丁二酰异羟肟酸衍生物 肽脱甲酰基酶抑制剂 抗菌活性 

分 类 号：R978.1[医药卫生—药品] R914.5[医药卫生—药学]