Design of novel amidoxime ketolide core and an efficient synthesis of WCK 4763: for treatment of gram-positive pneumococci

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 C 3 keto function after the replacement of cladinose sugar unit followed by oxidation. The early ketolide compounds are composed of 11,12 carbamate group and C 11-12 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