Quinolone molecular structure-activity relationships: What we have learned about improving antimicrobial activity

Recently, understanding of how molecular modifications of the core quinolone structure affect(s) antimicrobial agent activity has progressed rapidly. Three positions (2, 3, and 4) cannot be changed without a significant loss of biological activity. Furthermore, it appears that a cyclopropyl group is optimal at position 1. Substituents at positions 5 and 8 affect planar configuration, and either a methyl or methoxy appear optimal at these sites. Hydrogen and amino groups have been investigated as useful substituents at position 6, replacing the fluorine of the fluoroquinolones. Interestingly, in vitro activity enhancement observed with alterations at positions 5 and 6 is not always accompanied by improved in vivo action. For all these modifications, the substituents at positions 7 and 8 are critical for potent antimicrobial activity. Optimizing overall molecular configuration enhances the number of intracellular targets for antimicrobial action (R-8) and impedes the efficiency of efflux proteins (R-7) that diminish intracellular penetration.