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.

Keywords:

• Antibiotic
• macrolactone
• macrolide
• clarithromycin
• benzoxaborole
• 1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole
• antibacterial
• conjugates of antibiotics

Acknowledgements

We are sincerely thankful to Ms Malyutina (from Gause Inst. of New Antibiotics) for HPLC of samples. Additionally, we are grateful to Dr. A.M. Korolev and Dr. Yu.M. Luzikov (both from Gause Inst. of New Antibiotics) for ESI-MS and NMR spectra as well as very intelligent conversation and friendly advices.

Disclosure statement

The authors report no declarations of interest.