Ketolides are the fourth generation semisynthetic macrolides derived from erythromycin A, designed to address the limitations of currently available drug treatments including penicillins, macrolides and glycopeptides. Ketolides-the next generation macrolides antibiotics are deliberate to pass the issues of bacterial resistance by introducing keto function at C3 position of macrocycle through the replacement of l-cladinose sugar moiety and brings a broader spectrum of activity. The original research work reported here covers, structure activity relationship based design and synthesis of 34 novel ketolide molecules, are subsequently subjected to desired microbial evaluations. Through this exercise; WCK 4873 (Nafithromycin) has been emerged as clinical candidate among the four different series synthesized. Nafithromycin, consists of novel amidoxime function bearing 2-pyridine-1,3,4-thiadiazole biaryl side chain set apart through a four atom spacer containing a cis double bond and a chiral methyl. This non-flexible spacer possibly aligns the biaryl ring system resulting in a favorable interaction with dual 23S rRNA targets exhibiting better potency to treat gram positive infections. WCK 4873 emerged as preclinical candidate based on in vitro studies, and animal model studies, it had successfully accomplished phase 1 and phase 2 clinical studies in United States, Europe and India. Currently, nafithromycin has acquired the status as phase 3 drug candidate having potential to fulfill the unmet medical needs for treatment of CABP infections.

酮内酯类是第四代半合成大环内酯类药物，衍生自红霉素 A，旨在解决目前可用药物治疗的局限性，包括青霉素、大环内酯类和糖肽类药物。酮内酯类——下一代大环内酯类抗生素，通过取代l ，在大环化合物C 3 位引入酮功能，解决细菌耐药性问题。-cladinose 糖部分并带来更广泛的活动范围。此处报告的原始研究工作涵盖了基于结构活性关系的 34 种新型酮内酯分子的设计和合成，随后进行了所需的微生物评估。通过这个练习；WCK 4873 (Nafithromycin) 已成为合成的四个不同系列中的临床候选药物。Nafithromycin，由带有 2-pyridine-1,3,4-thiadiazole 联芳基侧链的新型偕胺肟功能组成，侧链通过包含顺式的四原子间隔基分开双键和一个手性甲基。这种非柔性间隔子可能会排列联芳基环系统，从而与双 23S rRNA 靶标产生良好的相互作用，从而表现出更好的治疗革兰氏阳性感染的效力。WCK 4873成为基于体外研究和动物模型研究的临床前候选药物，已在美国、欧洲和印度成功完成1期和2期临床研究。目前，萘红霉素已获得 3 期候选药物的地位，有可能满足治疗 CABP 感染的未满足医疗需求。