The 2-pyridone antibacterial agents: 8-position modifications

Improved potency against multiply resistant streptococci and anaerobic microorganisms relative to current antibiotics has been sought by many laboratories around the world. As one result of attempts to prepare analogs of 4-quinolone anti-infectives bearing novel ring systems, the 2-pyridones were discovered. The 2-pyridones, which are bioisosteres of 4-quinolones, are highly active against a wide range of resistant strains of bacteria. Several hundreds of 2-pyridones have been synthesized incorporating modifications at various positions. In order to reduce the complexity of this review, only the widely adopted 8-position modifications (corresponding to the 7-position of the quinolones) will be discussed here. From scientific publications and patents, it is clear that many of the 2-pyridones are very promising candidates and yet only selective members of these compounds have been advanced to detailed preclinical trials. Among the promising candidates, A-170568 was demonstrated to have the best overall profile in terms of the in vitro and in vivo antibacterial activities, safety profile, and tissue penetration.