Abstract
The history of quinolone antimicrobial agents began when Lesher discovered Nalidixic acid (NA) in 1962. NA showed good antimicrobial activity against members of the family Enterobacteriaceae such as E. coli, and was primarily used for the treatment of urinary tract and gastrointestinal tract infections. Following the discovery and development of NA, numerous studies have been carried out to improve antimicrobial activity and spectrum, and the pharmacokinetic profile of NA derivatives. Further manipulation of the molecule produced new agents such as oxolinic acid, promidic acid and pipemedic acid (PPA) as antimicrobial activity increased and broadened during the period 1965-1975. In 1977, norfloxacin (NFLX), a new quinolone antimicrobial agent, was discovered. It possesses a fluorine atom at position 6 and a piperazinyl group at position 7 on the quinolone ring. NFLX demonstrated a broader spectrum and antimicrobial activity more than 10 times higher than NA and PPA against gram-negative bacteria including Pseudomonas aeruginosa and gram-positive bacteria, thereby providing good in vivo efficacy against animal infection models due to good tissue distribution. Phase 1 clinical studies of NFLX started in 1978 after confirming its safety in various animal toxicological studies, followed by phase 2 and 3 clinical studies. NFLX showed excellent clinical efficacies in urinary tract infections and GI tract infections, as well as upper respiratory tract infections, ear-nose-throat infections, and skin soft tissue infections owing to its potent antimicrobial activity and good tissue distribution. A good safety profile for NFLX was confirmed in these clinical studies. After the development of NFLX, many pharmaceutical companies began the R&D of new quinolone antimicrobial agents. Some of these compounds were successfully developed globally. New quinolones have become an essential antimicrobial agents in clinical settings and have gained an outstanding reputations for their excellent efficacies against various infections. In this review, I provide a retrospect regarding the discovery and development of NFLX, the forefront of new quinolone antimicrobial agents in the world.
