WCK 4873 (INN: Nafithromycin): Structure–activity relationship (SAR) identifying a novel lactone ketolide with activity against Streptococcus pneumoniae (SPN) and Streptococcus pyogenes (SPY)

Abstract

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.