Synthesis and biological activity of 5-amino- and 5-hydroxyquinolones, and the overwhelming influence of the remote N1-substituent in determining the structure-activity relationship

Article abstract of DOI:10.1021/jm00107a039

A series of 5-amino- and 5-hydroxyquinolone antibacterials substituted at C₇ with a select group of common piperazinyl and 3-aminopyrrolidinyl side chains was prepared. These 5-substituted derivatives were compared to the analogous 5-hydrogen compounds for antiinfective activity by using DNA gyrase inhibition, minimum inhibitory concentrations against a variety of bacteria, and in vivo efficacy in the mouse infection model. The influence on the structure-activity relationships of varied substituents at C₈ (H, F, Cl) and N₁ (ethyl, cyclopropyl, difluorophenyl) was also studied. The results showed that several of the structure-activity conclusions regarding side-chain bulk at C₇, the effect of halogen at C₈, and the effect of the C₅-amino group were greatly influenced by the choice of the N₁-substituent. Several outstanding broad spectrum quinolones were identified in this work. In particular, the spectrum and potency of the 7-piperazinyl quinolones could be greatly enhanced by the judicious choice of C₅-, C₈-, and N₁-substitutents.