Original article Synthesis and topoisomerase inhibitory activities of novel aza-analogues of flavones 1 Zhihua Sui*, Van N. Nguyen # , Jason Altom, Jeffrey Fernandez, Jamese J. Hilliard, Jeffrey I. Bernstein, John F. Barrett # , Kwasi A Ohemeng* # The R.W. Johnson Pharmaceutical Research Institute, 1000 Route 202 South, Raritan, New Jersey 08869, USA (Received 20 July 1998; accepted 29 October 1998) Abstract – A series of aza-flavones (3-hydroxy-2-phenyl-4-quinolones) were designed and synthesized as inhibitors of bacterial DNA-gyrase and mammalian topoisomerase II. Structure activity relationships of the compounds against each of the enzymes are discussed. © Elsevier, Paris aza-flavones / 3-hydroxy-2-phenyl-4-quinolones / DNA-gyrase / topoisomerase II 1. Introduction DNA topoisomerases catalyse the topological intercon- versions of DNA molecules which are required for several essential processes in DNA metabolism, includ- ing replication, recombination, transcription, and chro- mosome separation at mitosis [1]. These enzymes have therefore served as targets for several useful antitu- mour [2] and antibacterial agents [3]. Both prokaryotic and eukaryotic topoisomerase II inhibitors, developed as either antibacterial or antitumour agents, respectively, share a similar mechanism of action. The formation of a ternary complex (DNA::topoisomerase II::drug) leading to the “cleavable-complex” is required for the activity of the inhibitors [4–8]. Specific binding sites and strand specificity for covalent catalysis leading to formation of the ternary drug complex are unique, even though both enzymes share a common tyrosine for the covalent catalysis [9–13]. These differences afford the possibility of finding agents that inhibit only the prokaryotic topoi- somerase II, such as the antibacterial 4-quinolones [14–16], or inhibitors of the mammalian topoisomerase II, such as the antitumour quinolones [15, 17–21]. In the process of searching for prokaryotic topoi- somerase II (DNA gyrase) inhibitors, we recently identi- fied a series of flavones 1 as bona fide DNA gyrase (bacterial type II topoisomerase) inhibitors by the super- coiling and cleavable complex assays. Some of the compounds (e.g. quercetin: IC 50 = 3.3 μg/mL) were as potent as some of the currently marketed 4-quinolone antibacterials (e.g. ofloxacin: IC 50 = 1.75 μg/mL) against the target enzyme [22]. This led us to synthesize a series of the hitherto unknown aza-analogues of flavones 2 (figure 1). Since literature evidence indicated that some *Correspondence and reprints 1 Part of the work was presented at the XIVth International Symposium on Medicinal Chemistry, Maastricht, NL, 1996 (Abst. P-10.17) # Current address: Bristol-Myers Squibb Pharmaceutical Re- search Institute, 5 Research Parkway, Wallingford, CT 06492- 7660 Figure 1. Structures of flavones 1 and aza-analogues of flavo- nes 2. Eur. J. Med. Chem. 34 (1999) 381-387 381 © Elsevier, Paris