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首页> 外文期刊>The Journal of Antibiotics: An International Journal >Synthesis and structure activity relationships of novel lincomycin derivatives. Part 4: synthesis of novel lincomycin analogs modified at the 6-and 7-positions and their potent antibacterial activities
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Synthesis and structure activity relationships of novel lincomycin derivatives. Part 4: synthesis of novel lincomycin analogs modified at the 6-and 7-positions and their potent antibacterial activities

机译：新型林核糖素衍生物的合成与结构活性关系。 第4部分：在6-α和7位和它们有效的抗菌活性改性新型林霉素类似物的合成

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To modify lincomycin (LCM) at the C-6 and the C-7 positions, we firstly prepared various substituted proline intermediates (7, 11-15 and 17). These proline intermediates were coupled with methyl 1-thio-alpha-lincosamide and tetrakis-O-trimethylsilylation followed by selective deprotection of the TMS group at the 7-position gave a wide variety of key intermediates (23-27, 47 and 50). Then, we synthesized a variety of novel LCM analogs modified at the 7-position in application of the Mitsunobu reaction, an S(N)2 reaction, and a Pd-catalyzed cross-coupling reaction. Compounds 34 and 35 (1'-NH derivatives) exhibited enhanced antibacterial activities against resistant pathogens with erm gene compared with the corresponding 1'-N-methyl derivatives (3 and 37). On the basis of reported SAR, we modified the 4'-position of LCM derivatives possessing a 5-(2-nitropheny1)-1,3,4-thiadiazol-2-yl group at the C-7 position. Compound 56 showed significantly potent antibacterial activities against S. pneumoniae and S. pyogenes with erm gene, and its activities against S. pneumoniae with erm gene were improved compared with those of 34 and 57. Although we synthesized novel analogs by transformation of a C-7 substituent focusing on the 1'-demethyl framework to prepare very potent analogs 73 and 75, it was impossible to generate novel derivatives exhibiting stronger antibacterial activities against S. pneumoniae with erm gene compared with 56.
机译：为了在C-6和C-7位置进行改性LiNcomcin（LCM），我们首先制备了各种取代的脯氨酸中间体（7,11-15和17）。将这些脯氨酸中间体与甲基1-硫代-α-庚酰胺和四邻甲酰基甲硅烷化偶联，然后选择性脱保护7-位，得到各种关键中间体（23-27,47和50）。然后，我们在施用Mitsunobu反应的7-位进行了修饰的各种新型LCM类似物，S（n）2反应和PD催化的交叉偶联反应。与相应的1'-N-甲基衍生物（3和37）相比，化合物34和35（1'-NH衍生物）表现出对具有ERM基因的抗菌病原体的增强抗菌活性。在报道的SAR的基础上，我们修饰了在C-7位置的5-（2-NITROPENY1）-1,3,4-噻唑-2-基组的LCM衍生物的4'-位置。化合物56对S.肺炎肺炎和与ERM基因的肺炎氏细菌和S. pyogaenes的显着有效的抗菌活性。与34和57的相比，其对与ERM基因的肺炎肺炎的活动得到改善。虽然我们通过C-转化合成了新型类似物的新类似物7聚焦在1'-去甲基框架上制备非常有效的类似物73和75的取代基，不可能产生具有较强抗菌活性的新型衍生物与ERM基因相比，与56相比。

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