title: Two approaches to the use of benzo[c][1,2]oxaboroles as active fragments for synthetic transformation of clarithromycin.
abstract: Clarithromycin (active against Gram positive infections) and 1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole derivatives (effective for Gram negative microbes) are the ligands of bacterial RNA. The antimicrobial activities of these benzoxaboroles linked with clarithromycin at 9 or 4″ position were compared. Two synthetic pathways for these conjugates were elaborated. First pathway explored the substitution of the C-9 carbonyl group of macrolactone's cycle via oxime linker, the second direction used the modification of the 4″-O-group of cladinose via the formation of carbamates of benzoxaboroles. 4″-O-(3-S-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborole)-methyl-carbamoyl-clarithromycin showed twofold decrease in MICs for S. epidermidis and S. pneumoniae than clarithromycin. 4″-O-Modified clarithromycin demonstrated an efficacy against Gram positive strains only. Compounds with C-9 substitution were more active than 4″-O-substituted antibiotics for susceptible strains E. coli tolC and did not exceed the activity of initial antibiotics.
authors.affiliation: a Blokhin Cancer Center , Moscow , Russia.|b Pirogov Russian National Research Medical University (RNRMU) , Moscow , Russia.|c Gause Institute of New Antibiotics , Moscow , Russian Federation.
authors.forename: Gennady B
authors.initials: GB
authors.lastname: Lapa
authors.affiliation: c Gause Institute of New Antibiotics , Moscow , Russian Federation.
authors.forename: Elena P
authors.initials: EP
authors.lastname: Mirchink
authors.affiliation: c Gause Institute of New Antibiotics , Moscow , Russian Federation.
authors.forename: Elena B
authors.initials: EB
authors.lastname: Isakova
authors.affiliation: c Gause Institute of New Antibiotics , Moscow , Russian Federation.
authors.forename: Maria N
authors.initials: MN
authors.lastname: Preobrazhenskaya
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D001896:Boron Compounds / Q000737:chemistry / Q000494:pharmacology*; D066241:Carbon-13 Magnetic Resonance Spectroscopy; D017291:Clarithromycin / Q000737:chemistry / Q000494:pharmacology*; D006571:Heterocyclic Compounds / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D021241:Spectrometry, Mass, Electrospray Ionization
chemical_list: D000900:Anti-Bacterial Agents; D001896:Boron Compounds; D006571:Heterocyclic Compounds; D017291:Clarithromycin
keywords: 1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole; Antibiotic; antibacterial; benzoxaborole; clarithromycin; conjugates of antibiotics; macrolactone; macrolide