Ketolides are the next generation macrolides, which shows broad spectrum of activity against macrolide resistant species, Streptococcus pneumoniae and Streptococcus pyogenes. Ketolides are derived from Erythromycin A, as name indicates; it possesses a C3 keto function after the replacement of cladinose sugar unit followed by oxidation. The early ketolide compounds are composed of 11,12 carbamate group and C11-12 aryl alkyl or 6-O alkyl extension. Here we report, further essentials in ketolide antibacterial drug development program carried out at Wockhardt, wherein pioneering synthetic strategies of novel amidoxime ketolide core described in details. In addition the designing of biheteroaryl side chain, 2-(5-Bromomethyl-1,3,4-thiadiazol-2-yl)-pyridine and lead molecule synthesis (WCK 4763) is explained here exclusively. WCK 4763 was one of the preclinical developmental candidate, emerged from our novel ketolide antibacterial research showing excellent activities against panel of gram-positive pathogens. Development of WCK 4763, gave us broader understanding of mechanistic insight for improving the desired biological activities, which then paved the path for development of WCK 4873 (Nafithromycin).

Graphical Abstract

中文翻译：

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新型偕胺肟酮内酯核的设计和 WCK 4763 的高效合成：用于治疗革兰氏阳性肺炎球菌

酮内酯类是下一代大环内酯类，对大环内酯类耐药菌种、肺炎链球菌和化脓性链球菌表现出广谱活性。顾名思义，酮内酯来源于红霉素 A；cladinose糖单元置换后氧化，具有C 3 酮基功能。早期酮内酯化合物由11,12氨基甲酸酯基团和C11-12 芳基烷基或 6-O 烷基延伸。在这里，我们报告了在 Wockhardt 开展的酮内酯抗菌药物开发计划的进一步要点，其中详细描述了新型偕胺肟酮内酯核心的开创性合成策略。此外，双杂芳基侧链、2-(5-Bromomethyl-1,3,4-thiadiazol-2-yl)-pyridine 和先导分子合成 (WCK 4763) 的设计在这里专门进行了说明。WCK 4763 是临床前开发候选药物之一，来自我们的新型酮内酯抗菌研究，显示出对一组革兰氏阳性病原体的出色活性。WCK 4763 的开发让我们对改进所需生物活性的机制有了更广泛的了解，这为 WCK 4873（萘红霉素）的开发铺平了道路。

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