Two approaches to the use of benzo[c][1,2]oxaboroles as active fragments for synthetic transformation of clarithromycin

• Published in: Journal of enzyme inhibition and medicinal chemistry 2017-01, Vol.32 (1), p.452-456
• Main Authors: Lapa, Gennady B., Mirchink, Elena P., Isakova, Elena B, Preobrazhenskaya, Maria N
• Format: Article
• Language: English
• Subjects: 1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; antibacterial; Antibiotic; Antibiotics; benzoxaborole; Boron Compounds - chemistry; Boron Compounds - pharmacology; Carbon-13 Magnetic Resonance Spectroscopy; Carbonyl compounds; Clarithromycin; Clarithromycin - chemistry; Clarithromycin - pharmacology; conjugates of antibiotics; Heterocyclic Compounds - chemistry; Heterocyclic Compounds - pharmacology; macrolactone; macrolide; Models, Molecular; Ribonucleic acid; RNA; Spectrometry, Mass, Electrospray Ionization; Strains (organisms); Streptococcus infections
• ISSN: 1475-6366; 1475-6374
• DOI: 10.1080/14756366.2016.1261129

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.