The 2-pyridone antibacterial agents: Bacterial topoisomerase inhibitors

Many attempts have been made to prepare analogs of 4-quinolone antibacteria l agents bearing novel ring systems, which might retain the favorable prope rties of these widely used antibacterial agents and at the same time increa se activity against multidrug-resistant bacteria, streptococci, and anaerob ic microorganisms. One such attempt involved bioisosteric exchange of the 1 -N atom and 4a-C atom of naphthyridones, quinolones, and benzoxazines to pr oduce a family of highly active pyridopyrimidines, quinolizines, and ofloxa cin bioisosteres. These new antibacterial agents have born named collective ly as the 2-pyridones. Many hundreds of 2-pyridones have been synthesized a nd evaluated in vitro and in vivo, and selected members are advancing towar d human clinical trials, Preparation of these bioisosteres required the dev elopment of enabling chemistry, as previous methods were unsuccessful in pr oducing the needed core structures. This review compares the structure-acti vity relationships of these agents with known trends among 4-quinolones, fr om which it is seen that then 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 pro pel ties are posited to arise from electronic and conformational alternatio ns 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. (C) 2000 John Wiley & Sons, Inc.