title: Chemistry and biology of macrolide antiparasitic agents.
abstract: Macrolide antibacterial agents inhibit parasite proliferation by targeting the apicoplast ribosome. Motivated by the long-term goal of identifying antiparasitic macrolides that lack antibacterial activity, we have systematically analyzed the structure-activity relationships among erythromycin analogues and have also investigated the mechanism of action of selected compounds. Two lead compounds, N-benzylazithromycin (11) and N-phenylpropylazithromycin (30), were identified with significantly higher antiparasitic activity and lower antibacterial activity than erythromycin or azithromycin. Molecular modeling based on the cocrystal structure of azithromycin bound to the bacterial ribosome suggested that a substituent at the N-9 position of desmethylazithromycin could improve selectivity because of species-specific interactions with the ribosomal L22 protein. Like other macrolides, these lead compounds display a strong "delayed death phenotype"; however, their early effects on T. gondii replication are more pronounced.
authors.affiliation: Department of Chemistry, Stanford University, Stanford, California 94305, United States.
authors.forename: Younjoo
authors.initials: Y
authors.lastname: Lee
authors.forename: Jun Yong
authors.initials: JY
authors.lastname: Choi
authors.forename: Hong
authors.initials: H
authors.lastname: Fu
authors.forename: Colin
authors.initials: C
authors.lastname: Harvey
authors.forename: Sandeep
authors.initials: S
authors.lastname: Ravindran
authors.forename: William R
authors.initials: WR
authors.lastname: Roush
authors.forename: John C
authors.initials: JC
authors.lastname: Boothroyd
authors.forename: Chaitan
authors.initials: C
authors.lastname: Khosla
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology; D000977:Antiparasitic Agents / Q000737:chemistry* / Q000494:pharmacology*; D002478:Cells, Cultured; D006801:Humans; D018942:Macrolides / Q000737:chemistry* / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D021241:Spectrometry, Mass, Electrospray Ionization; D013329:Structure-Activity Relationship; D014122:Toxoplasma / Q000187:drug effects
chemical_list: D000900:Anti-Bacterial Agents; D000977:Antiparasitic Agents; D018942:Macrolides