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

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

Journal Name: Anti-Infective Agents
Formerly Anti-Infective Agents in Medicinal Chemistry

Volume 17 , Issue 2 , 2019

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Graphical 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 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.

Results and 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 the 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.

Wright, G.D. Antibiotics: A new hope. Chem. Biol., 2012, 19, 3-10.
Tevyashova, A.N.; Olsufyeva, E.N.; Preobrazhenskaya, M.N. Design of dual action antibiotics as an approach to search for new promising drugs. Russ. Chem. Rev., 2015, 84(1), 61-97.
Printsevskaya, S.S.; Reznikova, M.I.; Korolev, A.M.; Lapa, G.B.; Olsufyeva, E.N.; Preobrazhenskaya, M.N.; Plattner, J.J.; Zhang, Y.K. Synthesis and study of antibacterial activities of antibacterial glycopeptide antibiotics conjugated with benzoxaboroles. Future Med. Chem., 2013, 6, 641-652.
Schlünzen, F.; Harms, J.M.; Franceschi, F.; Hansen, H.A.; Bartels, H.; Zarivach, R.; Yonath, A. Structural basis for the antibiotic activity of ketolides and azalides. Structure, 2003, 11, 329-338.
Rock, F.L.; Mao, W.; Yaremchuk, A.; Tukalo, M.; Crepin, T.; Zhou, H.; Zhang, Y.K.; Hernandez, V.; Akama, T.; Baker, S.J.; Plattner, J.J.; Shapiro, L.; Martinis, S.A.; Benkovic, S.J.; Cusack, S.; Alley, M.R. An antifungal agent inhibits an aminoacyl-tRNA synthetase by trapping tRNA in the editing site. Science, 2007, 316, 1759-1761.
Lapa, G.B.; Mirchink, E.P.; Isakova, E.B.; Preobrazhenskaya, M.N. Two approaches to the use of benzo[c][1,2]oxaboroles as active fragments for synthetic transformation of clarithromycin. J. Enzyme Inhib. Med. Chem., 2017, 1, 452-456.
Adamczyk-Woźniak, A.; Borys, K.M.; Sporzyński, A. Recent developments in the chemistry and biological applications of benzoxaboroles. Chem. Rev., 2015, 115(11), 5224-4527.
Boron Science: New technologies and applications. Ed. by Hosmane N.S. 2011, CRC Press.
Hall, D.G. Boronic Acids: Preparation and applications in organic synthesis, medicine and materials, 2012, vol. 2, John Wiley & Sons.
Bubnov, Yu. Allylboranes: Principles of reactivity and application in organic synthesis. Vesn. Mos. Univ. Ser. Khim., 2005, 3, 140-154.
Bubnov, Y.N.; Kuznetsov, N.Y.; Pastukhov, F.V.; Kublitsky, V.V. Convenient method for the generation of allylic dihaloboranes and diallyl(chloro)borane and their application in the allylboration of alkenes and acetylenes. Eur. J. Org. Chem., 2005, 4, 4633-4639.
O’Donovan, M.R.; Mee, C.D.; Fenner, S.; Teasdale, A.; Phillips, D.H. Boronic acids-a novel class of bacterial mutagen. Mutat. Res. Genet. Toxicol. Environ. Mutagen., 2011, 724, 1-6.
Ciaravino, V.; Plattner, J.; Chanda, S. An assessment of the genetic toxicology of novel boron-containing therapeutic agents. Environ. Mol. Mutagen., 2013, 54 5, 338-346.
Skugor, M.M.; Stimac, V.; Palej, I.; Lugarić, D.; Paljetak, H.C.; Filić, D.; Modrić, M.; Dilović, I.; Gembarovski, D.; Mutak, S.; Eraković, H.V.; Holmes, D.J.; Ivezić-Schoenfeld, Z. Synthesis and biological activity of 4”-O-acyl derivatives of 14- and 15-membered macrolides linked to omega-quinolone-carboxylic unit. Bioorg. Med. Chem., 2010, 18, 6547-6558.
Ma, C.; Liu, Z.; Song, H.; Jiang, R.; He, F.; Ma, S. Synthesis and antibacterial activity of novel 11,12-cyclic carbonate azithromycin 4”-O-carbamate derivatives. J. Antibiot., 2010, 63, 3-8.
Mahrwald, R. Diastereoselection in lewis-acid-mediated aldol additions. Chem. Rev., 1999, 99(5), 1095-1120.
Nelson, S.G. Catalyzed enantioselective aldol additions of latent enolate equivalents. Tetrahedron Asymmetry, 1998, 9, 357-530.
Burkhardt, E.R.; Matos, K. Boron reagents in process chemistry: Excellent tools for selective reductions. Chem. Rev., 2006, 106(7), 2617-2650.
Nourse, J.G.; Roberts, J.D. Nuclear magnetic resonance spectroscopy. Carbon-13 spectra of some macrolide antibiotics and derivatives. Substituent and conformational effects. J. Am. Chem. Soc., 1975, 97, 4584-4594.
Noguchi, S.; Fujiki, S.; Iwao, Y.; Miurab, K.; Itai, S. Clarithromycin monohydrate: A synchrotron X-ray powder study. Acta Crystallogr., 2012, 8, 667-668.
Antonow, D.; Cooper, N.; Howard, P.W.; Thurston, D.E. Parallel synthesis of a novel C2-aryl pyrrolo [2,1-c][1,4]benzodiazepine (PBD) library. J. Comb. Chem., 2007, 3, 437-445.
VanVeller, B.; Aronoff, M.R.; Raines, R.T. A divalent protecting group for benzoxaboroles. RSC Adv., 2013, 3, 21331-21334.
Tevyashova, A.N.; Korolev, A.M.; Mirchink, E.P.; Isakova, E.B.; Osterman, I.A. Synthesis and evaluation of biological activity of benzoxaborole derivatives of azithromycin. J. Antibiot., 2018, 11, 103.
NCCLS-The National Committee for Laboratory Standards. Performance standards for antimicrobial susceptibility testing. NCCLS document M100-S15, USA, 2005.

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Article Details

Year: 2019
Published on: 05 July, 2019
Page: [99 - 104]
Pages: 6
DOI: 10.2174/2211352517666181122130101

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