title: In vitro anti-Mycobacterium avium activities of quinolones: predicted active structures and mechanistic considerations.
abstract: The relationship between the structures of quinolones and their anti-Mycobacterium avium activities has been previously derived by using the Multiple Computer-Automated Structure Evaluation program. A number of substructural constraints required to overcome the resistance of most of the strains have been identified. Nineteen new quinolones which qualify under these substructural requirements were identified by the program and subsequently tested. The results show that the substructural attributes identified by the program produced a successful a priori prediction of the anti-M. avium activities of the new quinolones. All 19 quinolones were found to be active, and 4 of them are as active or better than ciprofloxacin. With these new quinolones, the updated multiple computer-automated structure evaluation program structure-activity relationship analysis has helped to uncover additional information about the nature of the substituents at the C5 and C7 positions needed for optimal inhibitory activity. A possible explanation of drug resistance based on the observation of suicide inactivation of bacterial cytochrome P-450 by the cyclopropylamine moiety has also been proposed and is discussed in this report. Furthermore, we confirm the view that the amount of the uncharged form present in a neutral pH solution plays a crucial role in the drug's penetration ability.
authors.affiliation: Chemistry Department, Case Western Reserve University, Cleveland, Ohio 44106.
authors.forename: G
authors.initials: G
authors.lastname: Klopman
authors.forename: J Y
authors.initials: JY
authors.lastname: Li
authors.forename: S
authors.initials: S
authors.lastname: Wang
authors.forename: A J
authors.initials: AJ
authors.lastname: Pearson
authors.forename: K
authors.initials: K
authors.lastname: Chang
authors.forename: M R
authors.initials: MR
authors.lastname: Jacobs
authors.forename: S
authors.initials: S
authors.lastname: Bajaksouzian
authors.forename: J J
authors.initials: JJ
authors.lastname: Ellner
mesh_terms: D042462:4-Quinolones; D000890:Anti-Infective Agents / Q000494:pharmacology*; D006863:Hydrogen-Ion Concentration; D008826:Microbial Sensitivity Tests; D009162:Mycobacterium avium / Q000187:drug effects*; D013329:Structure-Activity Relationship
chemical_list: D042462:4-Quinolones; D000890:Anti-Infective Agents