Discovery of macrozones, new antimicrobial thiosemicarbazone-based azithromycin conjugates: design, synthesis and in vitro biological evaluation

Grgičević, Ivan; Mikulandra, Ivana; Bukvić, Mirjana; Banjanac, Mihailo; Radovanović, Vedrana; Habinovec, Iva; Bertoša, Branimir; Novak, Predrag

doi:10.1016/j.ijantimicag.2020.106147

Cited by 18 publications

(23 citation statements)

References 20 publications

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“…STD takes the difference of two experiments: off-resonance, with the irradiation frequency set far from any signal and on-resonance, where receptor resonances are selectively saturated. A difference spectrum, showing only resonances that experience saturation upon ligand binding, is obtained by subtracting the on-resonance spectrum from the off-resonance one, as shown in Figure 7 for 4"-aminopropyl azithromycin, which is a precursor for obtaining the novel class of bioactive azithromycin conjugates, the macrozones [66]. Then, STD enhancements are calculated using Equation (1):…”

Section: Probing Macrolide Interactions By Nmr Spectroscopymentioning

confidence: 99%

“…Grgičević et al have recently reported on the use of molecular modeling and NMR studies to design and characterize a novel hybrid class of bioactive azithromycin derivatives, the macrozones [66]. Interactions and binding properties of selected azithromycin-thiosemicarbazone conjugates to the ribosomal 23S rRNA were investigated by an in silico by docking study that led to the discovery of new potent macrolide compounds called macrozones.…”

Section: Probing Macrolide Interactions By Nmr Spectroscopymentioning

confidence: 99%

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Advanced Methods for Studying Structure and Interactions of Macrolide Antibiotics

Jednačak

Mikulandra

Novak

2020

IJMS

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Macrolide antibiotics are macrocyclic compounds that are clinically used and prescribed for the treatment of upper and lower respiratory tract infections. They inhibit the synthesis of bacterial proteins by reversible binding to the 23S rRNA at or near the peptidyl transferase center. However, their excellent antibacterial profile was largely compromised by the emergence of bacterial resistance. Today, fighting resistance to antibiotics is one of the greatest challenges in medicinal chemistry. Considering various physicochemical properties of macrolides, understanding their structure and interactions with macromolecular targets is crucial for the design of new antibiotics efficient against resistant pathogens. The solid-state structures of some macrolide-ribosome complexes have recently been solved, throwing new light on the macrolide binding mechanisms. On the other hand, a combination of NMR spectroscopy and molecular modeling calculations can be applied to study free and bound conformations in solution. In this article, a description of advanced physicochemical methods for elucidating the structure and interactions of macrolide antibiotics in solid state and solution will be provided, and their principal advantages and drawbacks will be discussed.

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Section: Probing Macrolide Interactions By Nmr Spectroscopymentioning

confidence: 99%

Section: Probing Macrolide Interactions By Nmr Spectroscopymentioning

confidence: 99%

Advanced Methods for Studying Structure and Interactions of Macrolide Antibiotics

Jednačak

Mikulandra

Novak

2020

IJMS

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“…Macrozones belong to a novel class of azithromycin–thiosemicarbazone conjugates that exhibit very good antibacterial activities against both susceptible and some resistant bacterial strains, such as efflux- and MLS (macrolides–lincosamides–streptogramines)- resistant S. aureus , S. pneumoniae and S. pyogenes strains [ 1 , 2 ]. Macrolide antibiotics, such as azithromycin, have been in clinical use for over 50 years, mostly due to their high efficacy, safety and favorable pharmacokinetics.…”

Section: Introductionmentioning

confidence: 99%

“…As above mentioned, macrozones are novel hybrid azithromycin derivatives designed to overcome bacterial resistance [ 1 , 2 ]. Structurally, they consist of a polyfunctional macrolactone ring with two saccharide units (desozamine and cladinose) and a thiosemicarbazone moiety attached to it at certain positions ( Scheme 1 ).…”

Section: Introductionmentioning

confidence: 99%

Interactions of Aminopropyl–Azithromycin Derivatives, Precursors in the Synthesis of Bioactive Macrozones, with E. coli Ribosome: NMR and Docking Studies

et al. 2021

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The structure and interactions of several aminopropyl–azithromycin derivatives (1a–c) have been studied by using NMR spectroscopy and docking calculations. Compounds 1a–c are precursors in the synthesis of macrozones, novel bioactive azithromycin–thiosemicarbazone conjugates active against some resistant bacterial strains. Today, bacterial resistance is considered as one of the major threats to human health. Knowledge on drug binding mode and conformations is one of the key factors in the process of designing molecules to fight resistance. In solution state, compounds 1a and 1c exist in the 3-endo-folded-out conformation, while 1b adopts a classical folded-out conformation. 13C and 15N CPMAS NMR spectra pointed towards similar structures in the solid state. The transferred NOESY NMR spectra confirmed binding to the E. coli ribosome and suggest that dominant conformations in the bound state resemble those in the free one. STD experiments identified reactive groups of 1a–c in close contact with the ribosome resembling binding epitopes observed for the related 15-membered macrolides. Docking studies revealed that the studied compounds bind to the same ribosome binding pocket similarly to erythromycin in the crystal state, and that the binding is achieved through H-bonds and van der Waals interactions. The bound conformation is the same as determined by NMR. STD enhancements observed for methylene protons in the aminopropyl side chain indicate additional interactions which contribute to the overall binding energy.

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“…1 ) is an orally bioactive, highly effective, well-tolerated, broad-spectrum antibiotic used to treat infectious diseases caused by both Gram-positive and Gram-negative bacteria. In addition to its antibacterial properties, AZM also has antimalarial, anti-inflammatory, immunomodulatory, and antiviral effects [54] , [55] , [56] , [57] . AZM caught the world's attention in 2020 because it showed promising results in the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease, commonly known as COVID-19.…”

Section: Introductionmentioning

confidence: 99%

Charge-transfer complexation of TCNE with azithromycin, the antibiotic used worldwide to treat the coronavirus disease (COVID-19). Part IV: A comparison between solid and liquid interactions

Adam

Refat

Altalhi

et al. 2021

Journal of Molecular Liquids

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Discovery of macrozones, new antimicrobial thiosemicarbazone-based azithromycin conjugates: design, synthesis and in vitro biological evaluation

Cited by 18 publications

References 20 publications

Advanced Methods for Studying Structure and Interactions of Macrolide Antibiotics

Advanced Methods for Studying Structure and Interactions of Macrolide Antibiotics

Interactions of Aminopropyl–Azithromycin Derivatives, Precursors in the Synthesis of Bioactive Macrozones, with E. coli Ribosome: NMR and Docking Studies

Charge-transfer complexation of TCNE with azithromycin, the antibiotic used worldwide to treat the coronavirus disease (COVID-19). Part IV: A comparison between solid and liquid interactions

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