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Synthesis and SARs of novel lincomycin derivatives Part 5: optimization of lincomycin analogs exhibiting potent antibacterial activities by chemical modification at the 6- and 7-positions.
The Journal of Antibiotics ( IF 3.3 ) Pub Date : 2018-Feb-01 , DOI: 10.1038/ja.2017.114
Yoshinari Wakiyama , Ko Kumura , Eijiro Umemura , Satomi Masaki , Kazutaka Ueda , Yasuo Sato , Yoko Hirai , Yoshio Hayashi , Keiichi Ajito

In order to modify lincomycin at the C-6 and C-7 positions, we prepared target molecules, which have substituted pipecolinic acid at the 6-amino group and a para-substituted phenylthio group at the C-7 position, in application of palladium-catalyzed cross-coupling as a key reaction. As the result of structure-activity relationship (SAR) studies at the 6-position, analogs possessing 4'-cis-(cyclopropylmethyl)piperidine showed significantly strong antibacterial activities against Streptococcus pneumoniae and Streptococcus pyogenes with an erm gene. On the basis of SAR, we further synthesized novel analogs possessing 4'-cis-(cyclopropylmethyl)piperidine by transformation of a C-7 substituent. Consequently, novel derivatives possessing a para-heteroaromatic-phenylthio group at the C-7 position exhibited significantly strong activities against S. pneumoniae and S. pyogenes with an erm gene even when compared with those of telithromycin. Finally, in vivo efficacy of selected two derivatives was evaluated in a rat pulmonary infection model with resistant S. pneumoniae with erm + mef genes. One of them exhibited strong and constant in vivo efficacy in this model, and both compounds showed strong in vivo efficacy against resistant S. pneumoniae with a mef gene.

中文翻译:

新型林可霉素衍生物的合成与合成孔径雷达(SAR)第5部分:通过在6位和7位进行化学修饰,对表现出有效抗菌活性的林可霉素类似物进行优化。

为了修饰在C-6和C-7位置的林可霉素,我们制备了在钯应用中具有6-氨基取代的胡椒酸和C-7位置的对位苯硫基的目标分子。 -催化的交叉偶联是关键反应。作为在6位上的结构-活性关系(SAR)研究的结果,具有4'-顺式-(环丙基甲基)哌啶的类似物对具有erm基因的肺炎链球菌和化脓性链球菌具有显着强的抗菌活性。在SAR的基础上,我们通过转化C-7取代基进一步合成了具有4'-顺-(环丙基甲基)哌啶的新型类似物。所以,即使与telithromycin相比,在C-7位上具有对-杂芳香族苯硫基的新型衍生物也对具有erm基因的肺炎链球菌和化脓性链球菌具有很强的活性。最后,在具有erm + mef基因抗性肺炎链球菌的大鼠肺部感染模型中评估了选定的两种衍生物的体内功效。在该模型中,它们之一显示出强而恒定的体内功效,并且两种化合物对具有mef基因的抗性肺炎链球菌均显示出强大的体内功效。
更新日期:2017-11-01
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