The 2-pyridone antibacterial agents: bacterial topoisomerase inhibitors

• Published in: Medicinal research reviews Vol. 20; no. 4; pp. 231 - 293
• Main Authors: Li, Qun, Mitscher, Lester A., Shen, Linus L.
• Format: Journal Article
• Language: English
• Published: New York John Wiley & Sons, Inc 01.07.2000; Wiley
• Subjects: Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Antibacterial agents; Antibiotics. Antiinfectious agents. Antiparasitic agents; antiinfective agents; Bacteria; bacterial resistance; benzoxazines; bioisosteres; Biological and medical sciences; DNA gyrase inhibitors; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; fluoroquinolones; Humans; in vitro activity; in vivo activity; Medical sciences; Microbial Sensitivity Tests; naphthyridinones; Pharmacology. Drug treatments; Pyridones - chemistry; Pyridones - pharmacology; pyridopyrimidines; quinolizines; Structure-Activity Relationship; Topoisomerase I Inhibitors; Pyridone derivatives; Treatment efficiency; Experimental study; In vitro; Infection; In vivo; Antibiotic; Chemotherapy; Treatment; Structure activity relation; Animal; Bacteriosis; Bacteria; Antibacterial agent; Pharmacokinetics; Quinolone derivatives
• ISSN: 0198-6325; 1098-1128
• DOI: 10.1002/1098-1128(200007)20:4<231::AID-MED1>3.0.CO;2-N

Many attempts have been made to prepare analogs of 4‐quinolone antibacterial agents bearing novel ring systems, which might retain the favorable properties of these widely used antibacterial agents and at the same time increase activity against multidrug‐resistant bacteria, streptococci, and anaerobic microorganisms. One such attempt involved bioisosteric exchange of the 1‐N atom and 4a‐C atom of naphthyridones, quinolones, and benzoxazines to produce a family of highly active pyridopyrimidines, quinolizines, and ofloxacin bioisosteres. These new antibacterial agents have been named collectively as the 2‐pyridones. Many hundreds of 2‐pyridones have been synthesized and evaluated in vitro and in vivo, and selected members are advancing toward human clinical trials. Preparation of these bioisosteres required the development of enabling chemistry, as previous methods were unsuccessful in producing the needed core structures. This review compares the structure‐activity relationships of these agents with known trends among 4‐quinolones, from which it is seen that there are many parallels, but also some significant departures as well. Generally, 2‐pyridones are more highly active in vitro and in vivo and more water soluble than comparable 4‐quinolones. These properties are posited to arise from electronic and conformational alternations in these new substances. Selected members show excellent pharmacodynamic properties, justifying the view that this is a very promising new class of totally synthetic antibacterial agents. © 2000 John Wiley & Sons, Inc. Med Res Rev, 20, No. 4, 231–293, 2000