title: Structure-property relationship for cellular accumulation of macrolones in human polymorphonuclear leukocytes (PMNs).
abstract: Macrolones are a new class of antimicrobial compounds consisting of a macrolide scaffold linked to a 4-quinolone-3-carboxylic acid moiety via C(4″) position of a macrolide. As macrolides are known to possess favorable pharmacokinetic properties by accumulating in inflammatory cells, in this study we determined the intensity of accumulation in human polymorphonuclear leukocytes (PMNs) of 57 compounds of the macrolone class and analyzed the relationship between the molecular structure and this cellular pharmacokinetic property. Accumulation of macrolones ranged from 0 to 5.5-fold higher than the standard macrolide azithromycin. Distinct structural features in all three considered molecule parts: the macrolide scaffold, quinolone moiety and the linker, affect cellular accumulation. Interestingly, while the parent macrolide, azithromycin, accumulates approximately 3-fold more than clarithromycin, among macrolones all clarithromycin derivatives accumulated in PMNs significantly more than their azithromycin counterparts. Modeling cellular accumulation of macrolones with simple molecular descriptors, as well as with the measured octanol-water distribution coefficient, revealed that the number of hydrogen bond donors and secondary amide groups negatively contribute to macrolone accumulation, while lipophilicity makes a positive contribution.
authors.affiliation: GlaxoSmithKline Research Centre Zagreb Ltd., Prilaz baruna Filipovića 29, HR-10000 Zagreb, Croatia. vesna.munic@glpg.com
authors.forename: Vesna
authors.initials: V
authors.lastname: Munić Kos
authors.forename: Sanja
authors.initials: S
authors.lastname: Koštrun
authors.forename: Andrea
authors.initials: A
authors.lastname: Fajdetić
authors.forename: Martina
authors.initials: M
authors.lastname: Bosnar
authors.forename: Željko
authors.initials: Ž
authors.lastname: Kelnerić
authors.forename: Višnja
authors.initials: V
authors.lastname: Stepanić
authors.forename: Vesna
authors.initials: V
authors.lastname: Eraković Haber
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology*; D002478:Cells, Cultured; D006801:Humans; D018942:Macrolides / Q000737:chemistry* / Q000494:pharmacology*; D009504:Neutrophils / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D018942:Macrolides