N-芳酰基-L-氨基酸异羟肟酸衍生物的设计、合成及抗革兰阴性菌活性研究

Design,synthesis,and biological evaluation of N- aroyl-L-amino acid hydroxamic acid derivatives as Gram-negative antibacterial agents

目的设计合成一系列N-芳酰基-L-氨基酸异羟肟酸的衍生物,以期得到抗革兰阴性菌活性较好的新化合物。方法以4-溴苯甲酸为起始原料,通过三甲基硅烷保护、去保护、缩合反应、偶联反应以及羟胺化反应,得到目标化合物6a~6x,经过1H-NMR、13C-NMR、HRMS确证结构;采用微量肉汤稀释法,对所有目标化合物在革兰氏阴性菌大肠杆菌和铜绿假单胞菌两种菌株上进行抗菌活性测试。结果合成了24个目标化合物,其中化合物6b、6p、6r对大肠杆菌和铜绿假单胞杆菌都表现出较强的抗菌活性;6a等13个化合物对大肠杆菌表现出较强活性,但对铜绿假单胞杆菌没有活性。结论该系列化合物结构中,R1和R2基团为活性可变基团,可进一步对其进行结构优化。

A series of N-aroyl-L-amino acid hydroxamic acid derivatives were designed and synthesized to provide new compounds with better anti-Gram-negative bacteria activity.Starting from 4-bromobenzoic acid,the target compounds 6 a-6 x were obtained through trimethylsilane protection,de-protection,condensation,alkynyl coupling and hydroxylamination reaction of ester group.The structures of the target compounds were confirmed by 1H-NMR,13C-NMR and HRMS.All the target compounds were tested on two strains of Gram-negative E.coli and P.aeruginosa by microbroth dilution method.Among which,compounds 6 b,6 p and 6 r showed good antibacterial activity both against E.coli and P.aeruginosa,and 13 compounds showed good activity against E.coli.The results of SARs showed that R1 and R2 groups were active variable groups,which can be further modified.