Deboronation of New Clarithromycin-Benzo[c][1,2]oxaborole Conjugates

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Author(s): Gennady B. Lapa*, Elena B. Isakova, Elena B. Mirchink, Maria N. Preobrazhenskaya.

Journal Name: Anti-Infective Agents

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Abstract:

Background: The conjugates of antibiotics are new molecules that might show new antibacterial spectrum and overcome resistance of insusceptible bacterial strains. Modification of known antibiotics like Clarithromycin with active fragments is laborious and proven method to overcome the resistance of such strains. Methods: The conjugates of Clarithromycin and Benzo[c][1,2]oxaboroles were synthesized using long linkers to extend antimicrobial spectrum of this antibiotic. Discussion: Unexpected intramolecular deboronation of these bioconjugated was found to occur when the linker contained two or more CH2-groups. Molecular modeling was used to understand the source of instability and show a possibility of intramolecular complex of carbonyl group at C-9 in Clarithromycin core and hydroxy-borole moiety. This could facilitate nucleophilic attack of methanol used in reactions to destroy benzo[c][1,2]oxaboroles fragments and leave stable hydroxyl- aryl molecules. Conclusion: The loss of boron from benzo[c][1,2]oxoborole fragments leads to a significant decrease of antimicrobial activity of synthesized antibiotics.

Keywords: macrolactone, macrolide, clarithromycin, benzoxaborole, 1-hydroxy-1, 3-dihydroben-zo[c][1, 2]oxaborole, antibacterial, conjugates of antibiotics, deboronation

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Article Details

(E-pub Ahead of Print)
DOI: 10.2174/2211352517666181122130101