创新霉素前药衍生物的合成及抗菌活性研究

Synthesis and antibacterial activity evaluation of Chuangxinmycin prodrugs

目的合成创新霉素前药衍生物,测定其体外抗菌活性。方法以创新霉素为起始原料,经酯化或酰胺化反应得到目标化合物1a^f和2a^f。结果共合成12个创新霉素前药衍生物,其结构均经核磁共振氢谱和质谱确证;化合物1a^e体现了较强的体外抗甲氧西林敏感金葡菌(MSSA)、耐甲氧西林金葡菌(MRSA)、甲氧西林敏感表葡菌(MSSE)、耐甲氧西林表葡菌(MRSE)和肺炎链球菌(ATCC49619)活性,其中化合物1a、1e体外抗MSSA、MRSA、MSSE、MRSE、ATCC49619活性是创新霉素的4~128倍,相当或略优于阳性对照药替甲环素。结论在创新霉素的C-2羧酸上形成取代苯甲酰氧甲酯或环己基甲酰氧甲酯前药有利于提高体外抗革兰阳性菌活性,化合物1a、1e的体内抗菌活性值得进一步研究。

Objective To synthesize and evaluate the in vitro antibacterial activities of Chuangxinmycin prodrugs. Methods Compounds 1a- f and 2a- f were synthesized via esterification or amidation of Chuangxinmycin. Results The structure of 12 Chuangxinmycin prodrugs synthesized in this paper was confirmed by 1H-NMR and MS. Compounds 1a- 1e showed potent antibacterial activity against MSSA, MRSA, MSSE, MRSE and ATCC49619. The antibacterial activities of compounds 1a, 1e against MSSA, MRSA, MSSE, MRSE,ATCC49619 were 4 to 128-fold stronger than that of Chuangxinmycin, and similar to or stronger than that of Tigecycline. Conclusion Prodrugs with a C-2 carboxyl benzoyloxy methyl ester or cyclohexanecarboxyloyloxy methyl ester of Chuangxinmycin are favorable for increasing the in vitro antibacterial activities on Gram-positive bacteria. The in vivo antibacterial activities of compounds 1a and 1e deserve further investigation.